Hello everyone. Hope you well, and you've enjoyed the webinar so far. So yeah, welcome to this webinar.
This is webinar 4, and we're gonna update on the management of some selected immune mediated diseases. So we'll go through a couple of the most commonly seen immune-mediated diseases being immune-mediated hemolytic anaemia and also immune mediated thrombocytopenia, but a lot of what we say around the sort of pathophysiology, but especially around the treatment when we talk about the immunosuppressive drugs, is going to be relevant to Any other immune mediated diseases you might come across. There's not actually all that many out there, but maybe something like immune-mediated polyarthritis might be another one that you, you will see.
Of course, there's immune-mediated skin diseases which you may occasionally see in practise, but they're out of the scope of what we're gonna be discussing in this particular webinar. So, immune-mediated diseases occur when there's dysfunction of the immune system, and we sometimes see that as part of the pathogenesis of inflammatory diseases, infectious diseases, neoplastic diseases, hence. In patients with immune-mediated diseases, we always go, or we tend to go looking for inflammatory infectious or neoplastic diseases, and the immune dysfunction is thought to be secondary to that underlying disease or condition.
But, despite extensive investigations, sometimes we don't find an underlying cause and so we say those patients have primary or sometimes referred to as idiopathic or autoimmune disease, so there's no known underlying cause. And there's lots of factors that predispose animals to developing autoimmune disease. We know that genetics is an important factor, particularly the cells that control the immune system, so those, MHC molecules, which are, molecules on the surface of cells that present antigens.
And probably hence why we see, certain breeds of dog and to some degree cat that are more or sometimes less predisposed to certain immune-mediated diseases. Of course, the, you know, spaniel is one that jumps out to you, that's predisposed to IMHA and also to ITP. Hormonal backgrounds, so we often see immune-mediated diseases more commonly in female animals.
We usually see, animals with primary disease at a younger age. Maybe those with secondary disease are possibly more likely to be a little bit older, particularly thinking about neoplasia as an underlying cause. Yeah, there can be things that alter the immune system and there's definitely environmental factors, .
Won't dwell on vaccines, but the take home message is that there's no good, strong evidence, particularly in the two diseases we'll talk about today, that vaccines are implicated in the cause of the disease. So I always encourage owners to continue with vaccinations. If an animal was vaccinated, you know, within a few weeks prior to developing an immune mediated disease.
Again, that's probably just coincidence. But it might make sense for you to suggest, you know, a different vaccine manufacturer brand when that animal comes to be re-vaccinated. Well, I definitely don't stop with stop vaccines, stop andalmenttic treatments, you know, there's plenty of preventable diseases out there that it's important to continue to prevent.
So this is a case example. This is Max, 5 year old male neuter Dalmatian, came to see us with a relatively short history of quite non-specific signs on clinical examination. He was dull, he was, depressed.
Importantly though, there was Iris or Jaundice of mucous membranes, and also of his sclera. His heart rate was increased 185 beats per minute. And when you palpated his abdomen, his spleen appeared enlarged.
It was very prominent on, on physical examination. Just an idea of the, jaundice that you can see on his, on his sclera. You tend to pick it up first on the sclera, then on the mucous membranes, then on the skin.
The level that you can appreciate jaundice depends on the animal and pigmentation of the animal and also on your eyesight as well. So it is quite variable. So we admitted Max for further investigations and we thought about his problems.
Again, I'll encourage you to do this in any cases that you have, particularly the more complicated cases or a case that's been passed between multiple clinicians and you. Trying to figure out what's going on, or a case that you've seen on behalf of another practise maybe. So I've sort of divided these into the maybe what you'd call primary problems at the top, and then the sort of secondary non-specific ones at the bottom.
Then you can maybe stop the webinar at this point and just think about some differential diagnosis, which is the next step in this problem orientated approach for problems like jaundice. So I'm sure these are some of the things you will have come up from the sort of groups in three categories pre-hepatic, hepatic and post-hepatics. So pre-hepatic is hemolysis.
There's obviously a number of different triggers to hemolysis that we'll touch on. Hepatic causes are the primary liver diseases, so inflammatory, infiltrate of infectious neoplastics, so things like chronic hepatitis that we've previously discussed. Or in a cat, neutrophilic cholangitis, lymphocytic cholangitis, hepatic lymphoma.
And the postopathic is biliary tract obstruction, which is due to an inflamed or swollen pancreas, choleliths, other obstructions, sometimes obstruction in the duodenum, if there's a foreign body or significant inflammation that stops that bile draining into the duodenum. So how can we rule in rule out some of the differential diagnoses? Well, a simple, relatively simple thing to do to start with, of course, is assess the, the pack cell volume.
There may be other indications on your clinical exam that this patient's jaundiced could also have a reduced, number of red cells, i.e. Is anaemic.
So there may be pale mucous membranes, there may be a tachycardia, although, of course, tachycardia could be related to pain and fear, and heart disease and all the other things. Maybe there's poor, poor pulses. So there may be things on, on clinical exam, but measuring the PCV doing haematology is a pretty, pretty simple thing.
Just like there might be other things on clinical exam or in the history to suggest a hepatic cause like if you can feel an abnormal liver or there's a history of, you know, signs of chronic liver disease such as weight loss and vomiting and diarrhoea, PUPD. Or there may be signs on the examination of a postopathic cause, so there may be abdominal pain and you're thinking about obstruction as an example. So Max is significantly anaemic and of course in an anaemic patient we always need to know a critical thing, whether that's regenerative or whether that's non-regenerative, and we, we do that by looking at the machine generated values, but also particularly looking at a blood film, and we'll touch on both of those two, just, just to remind you.
So the features of regeneration are that the red cells are increased in size and they have less haemoglobin. So they're released from the bone marrow at an earlier stage, so they're larger, and also they've had less chance to take on haemoglobin. Other things that you will see, at least on the smear examination, is polychromatophils or polychromatophaia.
That's these larger bluer cells which have got, ribosomal RNA in there, which again are early cells. And theosotosis is variation in cell size, so that's reflecting the fact that you've got some of these bigger, bigger earlier cells, and then you may see things like nucledes, red blood cells and sometimes Heinz bodies as well can indicate regeneration. So this is just a blood smear from a dog, you can tell it's a dog cause it's central pallor to the red cells, most of them.
And this is non-regenerative anaemia, so the take home is that all the red cells are roughly the same size. You can see there's a few changes, so it's probably creation, particularly in the cells, towards the right of your image, which is just a, you know, a, a change that happens when the red cells are, get put in EDTA. Compared to this patient, which has got a regenerative anaemia, and you can see there's obvious variation in cell size.
And there's a cytosis, there's nucleated red blood cells, two of them towards the bottom. And, you can also see there's polychromasia, so these bigger blues slightly, so the bluer cells, difficult on a, you know, a projected PowerPoint image that you're looking at on the screen, but if you were looking down the microscope, it would appear with a bluish hue, so the one in the very centre there is a, is a good example, and there's others on, on both sides of the smear. But of course, a very, accurate, gauge to a very accurate measurement of regeneration is to determine the reticular cy counts.
And so some automated machines will do that for you, but otherwise you staining with specific stains, you won't see this type of appearance, and these are reticular sites on a normal diff. You need to stain with a super vital stain like new methylene blue. So the number of reticular sites can give you a very accurate quantification of the regeneration, and laboratories will give you certain values.
It might be the absolute reticulocy. It may be various sort of reticulocyte corrected reticulocyte count, reticulocyte indices, but they'll often give you a reference interval as well for you to tell it. Determine whether there is an appropriate regenerative response.
So always look at the regenerative response, be it reticulocytes, be it anisocytosis, be it polychromasia. Based on the severity of the anaemia, so an animal with significant anaemia, a significant anaemia should have a marked regenerative response, whereas a patient with only a very mild anaemia, of course, you only expect a relatively mild regenerative response. And the other critical thing to remember is, of course, that regeneration takes about 234 days or so to happen.
So in animals with really acute onset, anaemia that turns out to be regenerative, you may not see that on the initial presentation, so it'd be important to retest in, you know, 3 or 4 days' time. So these are Max haematology results, so I'll just give you a moment to have a look at those and again maybe stop the webinar if you want to spend a little bit more time working through them. You can see that Max's, yep, significant anaemia fits with the manual PCV that we ran, and that's reflected by the decrease in total red blood cells, haemoglobin and the hematocrit.
You can see that the cells are big, so there's an increased MCV and they've got less haemoglobin, so that looks quite classic for regeneration. Caveat is there are things that can change the MCV. So, cells swell up when they're put in EDTA so that can falsely elevate it.
And then sometimes we see conditions such as liver disease, for instance, when there's less haemoglobin in there. You'll also see that there's neutrophilia, so that's related to stress or inflammation or, infection. And I've actually showed, showed you this earlier, this is the blood smear from a regenerative dog.
In fact, it was for, for Max. So this would be another good time when it's worth stop in the presentation and just having a look and see whether you can identify the cells. So we feel that Max has got a regenerative anaemia, based on the MCV, MCHC.
This is the smear. I've already said to you that this fits with regeneration because you can see anisocytosis and also polychromasia. But what other, what other cells can you, can you see on there?
So, what else have we got? We've got some platelets scattered around, we've got nucleated red blood cells, pointed out the polychromatophy in the centre. We've got some of these howl jolly bodies, you can see one to the far right, bottom right.
That's a, a nuclear remnant, those dark blobs within the red cell, and you can see increased numbers of those, in an animal with regenerative anaemia because the, the, bone marrow is not a, doesn't have time to expel all the nucleus and so some of it gets, retained and appears as how jolly bodies. But probably one of the critical things that you may have made out, but again, it's difficult on an image that you're looking at on your screen that's, you know, taken through a microscope with a camera versus looking directly down the microscope at that fresh air dried blood smear yourself, is that there are some spherocytes, which are these smaller, more densely staining cells, so they, they should have lost their central pallor. And they should be spherical, hence spherocytes.
And you'll remember that those are red cells that the macrophage has come along and has taken a chunk of that er cell membrane, so it's shrunk to a smaller cell, and it's also lost its biconcave shape. And then in max we also check the reticocyte count, so there's a percentage in a reference interval and then a reticulocyte number and again a reference interval. So yeah, Max has got regenerative anaemia, you know, what are the two main differential diagnoses and what tests can you, can you do?
Well, of course, it's critical that we look at biochemistry as well, and you can see there's a number of abnormalities here. There's increases in the liver enzymes, and you'll remember from the earlier webinar that ALT is a marker of patocellular damage, and the same with AST, although those significant involvement of skeletal muscle damage causing elevations in AST and ALP is a marker of biostasis, biliary stasis. Will also increase in young animals with bone turnover and also with steroid administration.
The urea is an important one in an anaemic dog because high urea could suggest GI bleeding because of course, blood in the gastrointestinal tract is a, is a great protein meal. So look out for that, it may just suggest, you know, dehydration, pre-renal lasotemia. And then the total bilirubin's increased, but we know that because Max is, Max is jaundiced.
So the two, to go back to my question, the two big differentials for regenerative anaemia, of course, are blood loss and hemolysis. We sort of already know that Max is likely to have got hemolysis because of the presence of spherocytes, but you know, you can try and rule out blood loss from your history, from your clinical exam, because for a patient's PCV to drop to 15 relatively quickly, there's going to have to be significant blood loss. The other thing that's worth looking at is why it's sort of in blue on here is the total protein, because if an animal is losing blood, at least externally.
You will see a decrease in red cells, but also a decrease in protein. So look carefully at the protein in a patient that's anaemic when you're trying to decide between blood loss and hemolysis. In hemolysis, the protein levels shouldn't, shouldn't change.
But of course the other thing is that if you go back to our differentials, you know, Max was a jaundiced dog and we were trying to look for causes of jaundice and hemolysis is one of our big causes of jaundice, so it all fits, it all fits quite nicely. So these are differentials for, hemolysis. It can be immune-mediated red cell destruction, which is either primary or idiopathic or autoimmune, or secondary to a number of things.
Infectious diseases, less common in this country, but in those that have travelled, particularly like Eliia Canis or Babezia, particularly, occasionally Lismania. Oxidant damage, more common in cats and in dogs, particularly sort of onions and, and garlics, but other things like paracetamol, of course, in, in cats. We very occasionally see red cells that get damaged if there's electrolyte imbalances, but that's very uncommon.
There's occasionally breeds that have predisposition to hemolys their red cells, so things like pyruva kinase deficiency or phosphofructokinase deficiency in springer spaniels, but not that common and those animals normally present at quite a young age, very intermittent, sometimes can be mild-ish, destruction. And then trauma to the red cells, particularly red cells travelling through neoplastic tissue, through fibrin, if the patient's got DIC that can lead to fragmentation and, hemolysis of the red cells. But the top group, the immune mediated causes are definitely by far the most, the most common, but it's important to think about, you know, oxidants and the history, to think about the breed, particularly to think about infectious agents if the animal's travelled.
This is a, if this is a, super useful, . A CBM consensus statement on the diagnosis, and I'll just show the abstract later of the similar article on the treatment. So if you're interested in this condition, you know, have, have a look, it's freely, freely available.
It's from a few years ago now, but it's still very much up to date. So, Max appears to have a regenerative anaemia, appears to be his proteins are normal. We've found evidence of serviciis, appears to be hemolysis, so it lightly fits with immune-mediated hemolytic anaemia.
So how do we try and diagnose that? Well, spyrocytes, as we've already talked about, and I've just, put an extract of what that consensus statements about, says about the utility of, spyrocytes. So, particularly if you're finding, more than 5 spyrocytes per high powered field or immersion, field, that's, that's quite useful.
You don't often see spyrocytes with other things, the exception would be in animals that have had previous blood transfusions. In saline agglutination is another useful thing to do, or auto agglutination, so you'll have done that before as a slide just depicting it here. But it's critical that you not only view grossly as per the top right, but you, put a cover slip on and examine under the microscope because you need to distinguish the roo formation, which is depicted here, stacking of red cells like coins, that is a natural phenomenon.
From the random orientation and random clumping of red cells in a handful of red cells to many hundreds, which is true of glutination, so you can only do that by looking under the microscope. So a simple thing to do, very easy to do, one drop of blood, 2 drops of saline, or slight variations on that, on that theme. And we see a glutination when there's lots of antibodies that stick an animal's red cells together.
So again, this is how it may look grossly and how it may look under the microscope, so it's critical you look under the microscope as well. The sort of more technical, if you like, or in-depth way for looking for, agglutination is to do the Coombs test, which is where you take the patient red blood cells and you add anti-dog, IGM, IgG, IGA or complements, sometimes individually, but often, often mixed together, which is called a sort of the multivalent Coombs test. And what happens if the dog or cat red blood cells have got antibody antibody on the surface, so it's an antibody saying to the immune system that these red cells are foreign.
Your anti IgG using the example antibody that you add to the solution, sticks those antibodies and hence red cells together and so you see autoglutination. So again, that's just its schematically, you're adding anti-dog immunoglobulin in here and the end result is a glutination. That's why the Coombs test can be, excuse me, challenging to do in a patient that's already glutinating.
So for me, if they inhale and a glutination test, it's clearly positive. That's in essence, your diagnosis, you don't need to go on and do a Coombs test. So what about the sort of sensitivity, specificity, well, the sensitivity is quite variable, you know, sort of 60 to 80%, so, I, there can be false, false negatives, particularly if the steroid therapy, but the specificity is relatively good, but you can still occasionally see false positive results and Those are generally a low tighter result.
So if you're sending samples to an external laboratory for Coombs tests that you'll probably do, make sure they give you a tighter because we're really looking for the higher titers to be significant. So, you know, a 1 in 2 dilution, 1 in 41 in 8 is probably not clinically significant, whereas 1 in 1632 and above is likely to be a really significant result. So yeah, so those are some of the, the, the diagnostics, regenerative anaemia of, of immune-mediated hemolytic anaemia, it's usually regenerative.
We're finding evidence of sarrocytes, insulin agglutination, positive cooms testing. Occasionally, no, we don't find what we often don't find all of those things. Occasionally we don't find evidence of any one of those things which actually then makes the diagnosis very challenging, challenging to do.
IMHA is idiopathic in most dogs. It's sort of thought to be due to self-active stroke auto-reactive T cells, and the red cells get, removed either within the spleen, occasionally the liver as well. Or by blood monocytes, so either extravascular, spleen, liver, or intravascular, and extravascular is, is luckily more common and it does tend to be less severe than the intravascular, destruction.
Occasional cases, we've got destruction only going on in the bone marrow. We call them non-regenerative IMHA or pure red cell plasia or various other, other names. They're quite difficult to diagnose and they can be very difficult to, to manage.
So, yeah, there's a number of things that can trigger, the body attacking red blood cells, and some of these things we've, sorry, we've already talked about, talked about before. It may be there's something stuck on the surface of the red blood cell, like a, like a drug. It may be that there's an infectious agent that's got cross reactivity between protein.
Surface molecules on the infectious agent and the red blood cell, it may be that the infectious agent sticks the red blood cell, or maybe things damage the red blood cell and expose previously hidden antigens, but whatever happens then, The body is recognising those antigens on the surface of the red cell as foreign and causing destruction either in the spleen, liver, extravascular or within the circulation itself. So there's a number of breeds that are predisposed, we've already mentioned about spaniels, but some other breeds, but every breed of dog can develop IMHA. We see it normally in young, middle-aged, dogs, female more than males, possibly more prevalent in the summer months in occasional studies, and as I alluded to earlier on, there's no clear link with vaccination.
Sometimes it is secondary, sorry, to infectious agents or neoplasia, and that's why we often screen for those, with the former, particularly in patients that have travelled abroad. So we do some screening. Screaming in Max has got no travel history.
We did actually do a 4DX and found because of course you'll maybe remember there are one or two diseases that have been found to occur in dogs with no history of travel. E cannis has been reported in non-traveled dogs. It's very Uncommon, but, we may start to screen for these infectious diseases more and more.
We also did some screening radiographs and ultrasonography to look for neoplastic or inflammatory or infectious diseases, but I'll touch on the sort of relevance of those in a moment. So, yeah, these, these are the results. So thoracic radiographs, there were nothing on his abdominal ultrasound.
There was an enlarged spleen that we felt on clinical exam, and a smallish nodule in the, in there, which we did find the elasperrates and as we find very commonly in these animals with relatively small single or multiple nodules, it's just extra medullary hematopoiesis, so. And the spleen can start to produce new red blood cells in a healthy animal, but particularly in patients that are anaemic like Max. So yeah, we often screen, as I mentioned, for underlying triggers in patients with immune-mediated diseases, and these are just figures taken from that ACVM consensus statement.
So these are specific to IMHA in dogs and cats and. Basically, what this is saying is that, you know, there isn't much increased risk in patients with IML or sorry, you don't tend to identify neoplastic causes in patients with IMA IMHA, you know, above what you see in, in control, in control a in control animals. So that sort of dotted line is the sort of threshold, value for anything above that, and there's a, you know, slightly increased chance of identifying that particular disease or condition in this patient with IMHA, so probably the more relevant one on there is on the, the right-hand side in cats for lymphoma, leukaemia.
But it, we still often do screen for things like, like tumour, but, you know, maybe, maybe we shouldn't, and I think I would definitely, I would do it more in, you know, the, the right signalments of the older animal generally, although of course we can see lymphoma in younger animals. What about inflammatory conditions, we may look, may look for those, but at least in dogs, you know, there's nothing that's clearly associated in this, you know, population at least, or this is a sort of meta-analysis of different studies, whereas in the cat might be slightly different, possibly pancreatitis, calangangia hepatitis might lead to slightly increased risk of developing IMHA. Drugs, antimicrobials are on there in dogs.
That's probably TMPS, penicillins can also trigger new mediated destruction. And in cats, anti-thyroid drugs are a definite known risk factor for IMHA. So keep a, keep a lookout for cats on carbimazole or methimazole, developing IMHA.
So we did some screening, no history of drugs, no foreign travel. We did a 4DX as I alluded to. Nothing on diagnostic imaging.
Max is a sort of, you know, 5 year old dog, younger to middle aged. He is male, which is less common, 70% of dogs, approximately are female. So there's no underlying trigger, and we decided he'd got idiopathic or autoimmune or primary IMHA.
So yeah, how do we treat him, lots of different drugs out there and it sort of changes over the, over the years, and these are probably some that you're more familiar with that we tend to use in our practise, . And there's pros and cons for for most of these. The general take home is that prednisolone is probably the most effective, so, you know, unless there's a really good reason all dogs and cats with MHA should receive prednisolone.
But we may need to use adjunctive drugs, and again just referencing back this time it's the consensus statement on the treatment of IMHA which is published in the Journal of Veterinary Internal Medicine and is, you know, freely, freely accessible. So, do a, do a Google search, do a PubMed search for this and download that if you're particularly, particularly interested. So this is quite useful actually.
This is, I've just, taken this out of that consensus statement. So after diagnosis, Prednisolone again is a sort of critical, critical thing. But we sometimes go on to use a second drug and that might be if the animal's having very bad side effects to, steroids.
It might be if there's good reasons why you can't use steroids, which occasionally, maybe, maybe a diabetic is an example. But it may well be because we're not controlling, controlling the disease, and some people, including us, but we do tend to see the more severe cases start with a second immune and modulatory drug from the onset. But many of our cases have maybe failed steroids alone or, as I say, have got really severe, really severe disease.
And so this flow chart is maybe suggesting a period of about 7 days, but as before using a second drug, but as I say, if you've got severe side effects of steroids or the animals, you know, anaemia is really not being controlled and keeps dropping, and you need to use, you know, more than one blood transfusion, that's definitely a time to add in a second line drug. We've rarely add in a third line drug. We occasionally go on to other things that I'll touch on like IVIG, which is, All human immunoglobulins, you may have heard of that, you possibly may have, may have used it.
So, as I alluded to, glucocorticoids, ultimately prednisolone is the, the drug of choice. If you've got that patient hospitalised and it's not eating, then you might decide to use dexamethasone, but be careful because it is a very dexamethasone is a very ulogenic drug, so make sure you You check the dose that you're using, it's easy to just, you know, give a reasonable volume of this IV liquid, but you can cause a lot of GI ulceration, particularly in these dogs that have got hypoxic guts because they're anaemic and their circulation to their splenic circulation as their blood supply, sorry, to their splenic circulation has shut down. So in dogs, immunosuppressive dose is 2 milligrammes per kilogramme per day.
You may decide to split that 1 mg per gig BID. Some animals might tolerate that dose better. There's, you know, not, not good data, which is a, more efficacious thing.
ID or BID. Or if you have a dog that's over 25 kilogrammes, you might decide to use a milligramme per metre squared, so you just need to look online or in, you know, the BSAVA formary or or similar and work out how many metres squares that dog is and times that by 40. It's probably a better way to dose these bigger dogs, otherwise you overdose them with steroids and they can have very severe side effects, particularly things like muscle weakness and inability to rise.
So yeah, those are drugs, sorry, those doses in, in cats, they don't, don't tend to get so many side effects, so you can increase the dose a little bit, even up to the 4, although in reality, we, we rarely do that. So, yeah, what about the other big question we get in any immune-mediated disease is about, you know, what do you, how long do you keep the animals going for on, on the dose of immunosuppressive drugs, you know, how quickly, how slowly do you reduce them? Well, for IMHA, the consensus statement gives some, gives some suggestions and You know, maybe reducing once the PCB is, is stable and in the normal range, reducing the dose of prednisolone by about 25%, about every 33 weeks, and keeping going, importantly for several months, you know, that might be 4 to 8 months, and we definitely find that if the drugs, immunosuppressive drugs are stopped too early.
You know, particularly if they're stopped after a few weeks or so, and sometimes the disease does relapse again. So in any immune-mediated disease, wean slowly, and keep going for, for many months. What you wanna do though is, of course, keep going on a, a sort of a very low, maybe alternate day dose of drugs long term to minimise side effects.
So for we, for me when I'm deciding on. Dose reductions of say something like steroids, but it can be the other drugs as well. It's a balance between, you know, how well we're controlling the disease and the side effects.
So if we're controlling the disease very well, particularly if the animals having side effects, we're probably going to reduce the dose down more quickly, whereas, you know, if we're not controlling the disease, be it the platelet count, the red cell count, the joint diffusion in polyarthritis. We might decide to keep going at that high dose for a bit longer, or we might decide to add in a 2nd, 2nd drug. And the consensus statement suggests that there's a number of drugs that you can use, but didn't particularly recommend one or the other, so it's whatever you're really used to.
We tend to use cyclosporin most commonly, mycophenolate, occasionally rarely azathioprine and rarely lefronamide. Azathiorain for me is a sort of a, you know, relatively cost-effective drug, but studies have shown that in occasional animals, it can take significant amounts of time before it's fully effective, you know, 2, 2+ weeks, whereas we understand that cyclosporin works relatively quickly after you, after you give it. Azathioprine can also have a little bit of, myelosuppressive effects, particularly on the red cell, lines in the bone marrow, which is maybe less than ideal.
But you know, cyclosporin is good, but it does come at a significant cost, particularly in, in big animals. What other things might you want to do in the patient with IMHA? Well, you might need a blood transfusion, and you're gonna use a blood transfusion, of course, only in patients that actually require a blood transfusion.
So you're gonna look at clinic parameters, not. Just the PCB, but clinical parameters like Max is very tachycardic, he'd got weak pulses. He was, you know, lethargic and depressed and could hardly walk into the consulting room, so he's likely to be a candidate for a blood transfusion, whereas that patient that's maybe there.
Red cells have been slowly destroyed over a period of, you know, days to a week or more. They, you know, can compensate for their, lower numbers, lower numbers of red blood cells, so they're less, less likely. Human, IV immunoglobulin, so it, you may not have used it, but excuse me, occasionally we do.
We tend to use it as a sort of last resort, but . And that's probably, that's probably the way. Some people do use it much earlier on, but it can be quite expensive and does have side effects and can be difficult to, to get hold of.
So when you're giving human immunoglobulin, you're giving large amounts of pooled human immunoglobulins that that theoretically block the FC receptor on the macrophage or mononuclear. Cell to stop it binding onto the IGG that's bound on the dog IGG that's bound on this platelet that's marking it as foreign. So you're basically flooding the dog's body, with lots of human IGG.
But as I say, it can have some side effects and it is quite, quite expensive, so we use it infrequently and there's not good evidence that it's a, you know, a positive thing to, to use. Other things, animals that are significantly anaemic probably don't need oxygen. They need oxygen carrying capacity, i.e.
Haemoglobin. They, don't really need gastroprotectives, so you should try and minimise the drugs you're using these patients, so don't routinely give them, gastroprotectives. You know, the only time too is if there's clear evidence of already ulceration.
They don't, they're commonly used gastroprotectives like the H2 receptor antagonists cemetidine and ranitidine, or the proton pump, blockers like omeprazole, do not prevent steroids, or for that matter, non-steroidal induced ulceration. What about antithrombotics? You, if you're treating patients with the IMHA, you may have come across the use of antithrombotics, and we're using them more and more commonly nowadays because they, thrombotic or prothrombotic tendencies are definitely a significant cause of increased morbidity and mortality in dogs, at least with IMHA and probably, probably cats as well.
There's lots of reasons why some of them are, are listed on here, why patients with IMHA are, are predisposed to thromboembolic disease. And it's definitely been shown in a number of studies that their platelets become sort of. Over, overreactive and stick together and there's a number of articles, these are slightly older articles now, but you should be able to at least have a look at the abstracts here or online if you're, if you're interested.
And this is from the consensus statement. About what type of, what type of drugs you, you could use or should use. I must say that, and again, be cautious if the patient has very few platelets.
So it may be a dog that's got concurrent or a cat that's got concurrent, IMHA and ITP, so-called Evans syndrome, be very cautious about using any, any, antiplatelet drug in those guys, or any, anti-thrombotic drug. I must say we would tend to generally sort of jump further down that, that flow chart and use clopidogrel as our sort of antiplatelet drug. We don't use very much heparin or better unfractionated heparin that's got more sort of consistent pharmacokinetics and er dynamics.
So yeah, we tend to just use, clopidogrel, but possibly you'll have, you know, some experience of using the low molecular weights, heparins, or even, factor 10 inhibitors, not, not commonly used. And so there are studies that have looked at clopidogrel as a, you know, sensible anti antiplatelet drug, and so it's generally advisable that that that's used in patients with IMHA. So what happened to Max, we gave him prednisolone once a day orally, and then he was treated with cyclosporin, note the dose, 5 mg per kg BID, you may be used to using just a 5 mg per gig once a day dose and gradually reduced the dose.
He didn't have very many side effects actually of prednisolone, so we Didn't have to reduce the prednisolone too quickly for that reason, and so we reduced the drugs by about 25%, as I say, every 3 or 4 weeks, and then gradually reduced over about 4 or 5 month periods. He was put on clopidogrel, he did have a blood transfusion because he was quite severely affected. Also given IV fluids, symptomatic and supportive.
But also to keep blood flow to the kidneys and try and help dilute all this bilirubin that's circulating around that can damage his kidneys. And we kept him hospitalised for a few days until his PCV had risen, and he was relatively stable and, he was alive at least 2 years and had had no, no relapse to date. So that's IMHA.
Let's just flip over and think about immune mediated thrombocytopenia. We see quite a lot of cases with of immune mediated thrombocytopenia, and we get them definitely referred from primary care practise very frequently. So I'm sure you'll be seeing these, these cases in practise.
So a bit like IMH, well very similar to IMHA, there's, premature destruction of a cell type, in this case, platelets, . Usually in the spleen or the liver, occasionally in the circulation, because the body marks it as foreign and that might be because of things stuck to it, like drugs or infectious agents. It might be because we've exposed previously hidden antigens on the, on that platelet, but it's often due to unknown reasons.
And again, like in IMHA we've got primary or autoimmune or idiopathic disease when there's no known reason why that dog or cat's body is attacking its own platelets, and that's known as autoimmune or as I say, primary or idiopathic ITP or it can be secondary to a number of, number of causes. Infectious agents and drugs are the more common, just like for, for IMHA and . There's a whole load of different things, you know, you obviously don't need to remember these, you just look them up at the time you have a patient that you think has got ITP just to make sure there isn't a triggering factor.
If in doubt, try and stop any drugs, of course. We mentioned one or two of these in the context of IMHA. So they're very similar, potentiated sulfonamides, so TMPS, penicillins, occasionally other drugs.
Rarely that, you know, things like paracetamol and aspirin, and rarely for things like digitoxin, but they have all been reported. And there's certain infectious agents, luckily, the majority of them don't, you know, occur in this country, but things like Elia or riketsi reketsia or Boreela. Viral diseases can do, parasitic diseases can do, particularly any strong sorum has been linked with a sort of secondary ITP.
Occasionally we see it in other infectious or inflammatory diseases, and so again, that's why we go hunting often for infectious inflammatory or neoplastic diseases. So there's some examples on there, and there's some other miscellaneous causes. That, and again, vaccination like IMHA, there's no good evidence that triggers platelet, platelet destruction.
So, very similar to IMHA you have a antibody on the surface of your platelet or antibodies that then are seen by your mon nuclear cells, so particularly macrophages in the spleen, plus or minus the liver that remove that platelet from circulation. About the signalman, well, again, in dogs, sort of that, you know, young to middle age, females more than males, and again spaniels are in there, but one or two other breeds as well, but any breed of dog can get ITP. And cats again, sort of, you know, adult, middle aged, but no clear breed predispositions.
We rarely see ITP in cats, and to be honest, in my experience, it's often secondary to other things. We definitely see it in cats with FIV or FELV infection and cats with neoplastic, but occasionally other inflammatory conditions, but predominantly in a predominantly adult disease. Well, there are clinical signs, well, we see signs of a disorder of primary hemostasis, because of course platelets were involved in primary hemostasis, forming that initial platelet plug.
So things that are quite common are things like mucosal haemorrhages, so bleeding from the nose, bleeding from the mouth, sometimes bleeding from the bladder, from the, gut occasionally. We see ticia and ecchymosis, so particular, there's blood spots in that bottom photograph, you might see hy femur or retinal haemorrhage, and sometimes just spontaneous bruising or something or excessive bleeding from a venupuncture site sometimes. These animals that start to bleed excessively have need to have a, a significantly reduced platelet count, and it's often below 30 times 109, sometimes it's, you know, single figures to 0.
If the platelet count is above 30 times 10 to 9, it's probably not the cause of the animal's bleeding, although there is a bit of a grey zone between about 30 to 50 times 10 to 9. But, I often use a cutoff of 30 and below, but many patients with ITP have got very, very few platelets, single figures to zero. Make sure, of course, that if you do identify a, you know, reduced platelet count on your automated haematology result, results from your automated haematology machine, just remember that platelet clumping occurs very commonly, so that might be a false result.
So you should make fresh hair dryer blood smears, you should look at the the edge to start with the platelet clumps. That's where the big platelet clumps go. If you find platelet clumps, there's no point then going on to count the number of platelets.
You need to usually take a fresh blood sample, make a fresh smear, and examine that. If you don't find platelet clumps, move further back to the monolayer where cells are sort of spaced relatively evenly and not, you know, clumped on top of each other. And, count the number of platelets per high powered field, so, per oil immersion field, so that's 100 lens and times 10 IP, so times 1000.
And then you multiply that number by 15, or some people use 20 times 10 to 9. So take an average over several fields, multiply it by 15 to 20 times 109, that gives you your platelet count. So you're probably looking for a minimum of 1, you know, ideally 2, platelets, .
Or more per high powered field to, you know, take you above that sort of, you know, 30 times 10 to 9 count. Some people have historically looked in the bone marrow to try and work out if there might be a hidden disease in the bone marrow, like tumour or infectious agent, or to try and see whether there's evidence of the body attacking, platelets in the bone marrow. But it's usually because you're trying to find a, a reason why they're not getting produced, but it's of limited diagnostic utility.
So if you've got a patient with thrombocytopenia, you know, your question is, are those platelets getting produced? Are they getting destroyed, such as in ITP or possibly they're getting sequestered or used somewhere. And so, you can normally answer the question about if they're getting used by looking at the rest of the haematology, so patients that have got anaemia that might have gotten neutropenia as well.
It could be that there's, or it's more likely they've got bone marrow disease like an infection or a tumour in the bone marrow, or a drug that might affect the bone marrow, whereas a dog or a cat that's just got one cell lying decreased, like the platelets is very unlikely to have a bone marrow condition, hence why you don't go on and do a, a bone marrow sampling or biopsy. The other issue with trying to diagnose immune thrombocytopenia is it's a diagnosis of exclusion, because there isn't a good sort of, there isn't a sort of equivalent of a Coombs test for platelets. So there's no commercially available antiplatelet test.
So you rule out the other causes of thrombocytopenia, . And there's not lots of other causes thrombocytopenia out there, as I say, failure to produce in the bone marrow is one of the bigger causes, and reduced platelets because they've been used in clotting, so patients with things like disseminated intravascular coagulation, things like sequestration or loss in bleeding don't normally cause a significantly low platelet count, and definitely don't cause a platelet count that drops so low, the animals get clinical signs. So ultimately it is a a diagnosis of exclusion.
Have a look at the various causes of thrombocytopenia and try your best to try and rule out those because there isn't a definitive test for the immune-mediated destruction. How do we manage them? Well, again, and there isn't unfortunately, this time a sort of a good consensus statement on the management.
So it's often sort of anecdotal reports, you know, clinician experience is important. So, prednisolone again is the treatment of choice, similar, same doses as we talked about before, again, being careful with dexamethasone because it's a very ulogenic steroid. And then a number of other immunosuppressive drugs are out there, and as I say, there's not very good, clear evidence for which we would tend, because this is a very severe disease, you know, these patients can have catastrophic bleeds externally, or they can have catastrophic internal bleeds, you know, into like, say their central.
Nervous system. So we try and treat them relatively aggressively. So I would usually start with prednisolone plus another drug, and my choice is normally cyclosporin, occasionally mycophenolate if owners can't afford cyclosporin.
Azathioprine for me takes too long to to work in some dogs. So there are, papers looking at some of these, drugs. So this was a paper looking at, mycophenolates, plus steroids versus cyclosporin plus steroids, knowing that cyclosporin had been the drug that we'd use more commonly for these cases.
And it showed that, you know, it, it worked, . But for me, I think the problem with mycophenolate is you do see quite a lot of side effects, particularly, you know, GI GI side effects, so I maybe, maybe avoid it, but the generic mycophenolates, . I, you know, quite an affordable, affordable drug.
In this study actually the side effects in mycophenolate were less than seen in cyclosporin, it's often not my my view of the drug. So prednisolone plus or minus another immunosuppressive drug for me it's cyclosporin and I start that ASAP. The other thing that we give, there is some evidence for this, is fincristine, and we don't use it as a, you know, anti-cancer drug.
We don't use it as a sort of immunosuppressant in its, you know, in it's, you know, role that you may use it in, say, lymphoma. It's actually. Interferes with microtubual assembly, so basically causes the megacharocytes, which are the platelet precursors, to release their platelets early into the circulation.
So after you give it, you often see a, you know, a mild to sometimes moderate to occasionally marked rise in platelet numbers. And there's lots of reasons why that's, that's thought to happen apart from just its effects on the microtubules. People have argued though that you give this drug and it causes the platelet precursors to release platelets early and those platelets might not be functioning.
And also you're releasing those platelets into a, you know, an environment that's aimed at destroying them. So that's why some people have been a bit cautious historically about using this drug. If you do use it, you just give it as a one-off, textbook dose, 0.02 milligrammes per kilogramme, so it's a bit of a different dose you'd use in say a COP protocol.
And there are studies, this is from, you know, a year, many years ago now, but this was looking at fincristine as a single dose plus prednisolone versus just prednisolone in the treatment of ITP and these dogs had relatively ITP and the take home, you can hopefully read in the conclusions and clinical relevance in that Vin Christine was shown to have a positive outcome with a more rapid increase in platelet numbers and a decreased hospitalisation. So we tend to use it again just as a single drug. You must give it intravenously because of course any extruation can cause severe damage.
We talked about this in the context of IMHA so human immunoglobulin, so again, it's that pooled human immunoglobulin that basically floods the dog immunoglobulin receptors on your macrophage, or mononuclear cell to try and reduce the chomping of the, the dog's platelet or red blood cell. It's, there's not been very many studies looking at it, to be honest, in, in ITP. This was one actually looking at Vincristine versus human, IVIG.
And it didn't necessarily, it didn't really suggest that, IVIG was, you know, a particularly valuable drug to be used. And as I say, there are side effects and there's a significant, significant cost implications. So we uncommonly use it in patients with ITP.
We maybe use it as a sort of a last, last resort, salvage type of drug in the patients that are not responding to, to other things. The other thing you can do until your drugs start to work, and whichever drug you use is usually a bit of a delay, and as I say, you know, these patients can have critically low platelet counts and they can bleed into very important areas like the central nervous system. And you could give them platelets and until relatively recently, we couldn't do that, but the pet blood bank now supply.
Or in the last year or so, platelets concentrate, which is, platelets that have been separated from fresh whole blood. And it's a relatively, relatively small volume of platelets, or relatively small volume of product that contains all that platelets and it has negligible red cells and, and white cells. You tend to give 1 unit per 10 kilogrammes.
It's not hideously expensive, but of course a big dog, you might need to use several units and that does mount the cost. So we definitely use this. You, it's not something you can really keep keeping your practise stored.
You have to buy, get it, obtain it from the pet blood bank as as required. Although it does now have about a two-week shelf life, but we would only ever actually order it when we, when we need it. So it can make a big difference.
The platelet count can rapidly increase the platelet count and maybe just buy time for your drugs to start, start working. Just before we move on to that, the other thing you could consider is giving these patients whole blood. Don't give them pat red cells unless they, they, you know, they need red cells because they've lost blood because they're thrombocytopenic or maybe they've got concurrent IMHA but you can give them whole blood because whole blood does contain, you know, some platelets in there.
It's just often. You know, they've been been damaged during collection, and you have to give, you know, a big, a big volume of blood and whole blood is a very potent potent colloid. That whole blood can make a difference and can, can cause a platelet count to rise a bit more effective maybe in smaller animals, but then you're limited with the amount of blood that you can, you can give, you know, ideally you would give, you know.
Several whole bloods per dog, so one, you know, unit of whole blood per 10 kilogrammes, but that's a vast volume of, of a very potent colloid plasma in there is a potent colloid, so you get volume overload. So giving, you know, a unit of whole blood can make a difference. It can just cause a platelet count to rise that bit that maybe, you know, Stops bleeding in that patient, so don't discount whole, whole blood.
It's just that in biggish dogs you need to give quite a lot to significantly increase the platelet count, and it's not feasible to give many units to these patients because it causes volume, significant volume overload, apart from the issues getting hold of lots of blood, of course. And the other thing that we have occasionally done, for cases that are refractory to tick treatments, and we've done this in both ITP and IMHA is to do splenectomy. Now, obviously you're gonna be doing this as a sort of a salvage procedure.
It's not something you're gonna be doing in the first week that you're managing these patients, so. Animals that we sometimes see that really aren't responding very well to drugs or having severe side effects, or particularly as soon as you start to reduce the doses down of drugs, the disease relapse again. We've occasionally done splenectomy and had some, some success, so.
You know, once that patient's very stable and things, then could be something you consider, but you know, you're not gonna be doing it, doing it commonly. So I hope that was useful. We've been through, a couple of immune-mediated diseases, but a lot of what I've discussed, particularly when it comes to the drugs and the different drugs and the.
You know, dosing schedules and things are relevant to other immune-mediated diseases. Not that there's lots of other immune-mediated diseases you'll see very commonly, commonly in practise, but things like polyarthritis or the central nervous system, immune-mediated diseases, maybe you'll see, see occasionally. So the go to drug is, is prednisolone.
2 milligrammes per kilogramme per day for a dog, possibly a little bit higher than a cat, and we talked about adding in other drugs if the animal can't tolerate prednisolone, or if they've got very severe, severe disease. And we talked about the diagnosis of IMHA and I'd encourage you to look at that consensus statement and then also the diagnosis of ITP as well. So, I hope you found that, useful, and I look forward to seeing you for the next webinar.