Hello everybody and er welcome to today's session on medical emergencies, immune mediated hemolytic anaemia. So we're gonna talk about IMHA and it's mostly gonna pertain to dogs. We're gonna cover cats very sparingly really, for a variety of reasons that we'll touch on a little bit later on.
But why are we interested in IMHA? Well, it's an important cause of morbidity and mortality in dogs, and it's certainly something that I see very frequently, working in a referral centre with quite a large ECC, an emergency bias. That being said, you know, I do see a lot of patients with IMHA coming in, not through our emergency clinic, but also, as a more routine outpatient referral, with perhaps less severe or fulminant disease.
And that really, highlights the fact that IMHA patients really do come in all different flavours, OK. The vast majority of which are at least moderately unwell, you know, do require hospitalisation and relatively intense medical treatment. That being said, I think a lot of these patients can be managed in, first opinion or general practise really very successfully, and it's, it's the management of these guys in first opinion practise that I'm really going to concentrate on.
For this talk and to hopefully give you as many sort of top tips, of how to investigate and treat these guys successively successfully, give you a bit of an update on some of the latest information from the literature, as well, and then to highlight kind of some of those red flags that might make you think, well, this patient perhaps is a bit beyond, you know, the remit of what should be expected of the general practitioner and perhaps, you know, when to refer, OK? So it is relatively common, as I say, particularly in dogs. It does also occur in cats, but less commonly.
And when these guys present with IMHA they present with really severe anemias. And my last 5 to 10 cases, I, I can't remember any of them having had a PCV above 10%, but cats tend to cope incredibly well with low PCVs. So they're very interesting cases, but as I say, we're not going to talk about them too much today, they're a whole session from the time.
IMHA, as I'm sure you all know, can be primary or idiopathic in its nature, meaning that it's a primary autoimmune problem, with no, associated causes, and that's by far the most common form of IMHA that we see in dogs. But it may be a secondary IMHA, i.e.
Associated with an underlying or putative, trigger. And these cases, it's, it's really important to have quite a rapid and reliable diagnosis in these cases, so that we can differentiate it as early as possible from other causes of anaemia, so that we can rapidly institute, appropriate therapy, for these guys. So just to touch on the consensus statements of 2019, quite a lot of what I'm gonna mention in this session will be referencing information that's on these consensus statements.
And for those of you who aren't familiar with consensus statements, they are a series of documents that have been published by the American College of Veterinary Internal Medicine, through the Journal of Veterinary Internal Medicine, the JAVIM. And these, consensus statements are really, a really fantastic, appraisal and summary of all the information that's been published with regards, you know, to various diseases. So there's two consensus statements for IMHA.
The first one which is on the diagnosis, and that's in both cats and dogs, and then the second one which is on the treatment of IMHA which is just in dogs. I really, really highly recommend you get on, to this website, access the Journal of Veterinary, Internal Medicine, which is open access, so it's free to, to anybody. And you have a good look through these papers.
Have a look as well at the other consensus statements that are on there. There's some really nice consensus statements on other medical disorders such as, diagnosis and treatment of chronic hepatitis, diagnosis and treatment of mitral valve disease in dogs, etc. Etc.
So I just thought I'd put them up there just for those of you who aren't aware of this great resource and these specific papers which are well worth checking out. So moving on, to start to talk about a bit of the pathogenesis and pathophysiology of IMHA as I touched on on the first slide, we often refer to IMHA as a primary or secondary. So, primary IMHA, obviously those cases in which there is no underlying, cause that can be identified.
Now, the secondary patients are the ones in which there is an underlying condition that we believe is causing the IMHA. Now I use the term believe because it's often very, very hard in these patients to be absolutely 100% sure that this comorbidity, whether it be infection, neoplasia, drugs, for instance, whether or not that comorbidity, or that concurrent problem is the direct cause of the IMHA or it's just associated sort of with it. Now, As a result of that, one of the things that did come out of the consensus statements was that perhaps we should maybe change the way that we, name, IMHA from primary and secondary to actually associative and non-associative forms of the disease.
Yeah, and, and that's just sort of. Highlighting the fact that we're saying that this disease may be associated with another one, but we can't be 100% sure that it's definitely secondary to that other disease such as infection, neoplasia, and drugs. And this diagram here on the right is, is also from, the consensus statement, and that just helps highlight, that information really.
So we have these patients in which, there is no associated disease that's identified. This is the vast majority of our patients, which are essentially these primary IMHAs. And then we have the patients in which there is, a comorbidity identified, and they're the associative, cases.
And within those, I guess we're then saying, well, some of them we think very strongly that their underlying condition is triggering the IMHA and I'll mention a few of those more specific disorders just in a few slides. And then we have those patients in which actually that underlying comorbidity might just be an incidental one, OK? And we have to bear in mind as well that things are never that straightforward in internal medicine and that there is a lot of heterogenicity, OK, between patients who have, non-associative and associative disease.
So you can kind of lay anywhere, across the spectrum. And so potential associative causes that we, you know, commonly think about are infectious diseases, neoplasia, drugs, and potentially inflammation, vaccines. We're gonna touch on those, each slide by slide.
But a very brief way, I suppose, sorry, of, summarising. The way in which red cells are targeted and destroyed in IMHA is by thinking about, the actions of antibodies, OK. So with primary or non-associative IMHA, what we have are antibodies that are produced that directly target the antigens that are on the surface of our red blood cells, OK.
The antigens, sorry, the antibodies bind to the antigens, cause, agglutination. And then those agglutinated cells are destroyed, removed from the bloodstream. In, secondary or associative IMHA it's a little bit different, and instead, we get antibodies directly targeting microbial antigens that may be adhered to the red blood cell surface.
So the antibodies are targeting the bugs, but unfortunately because the bugs are stuck to red blood cells, they're destroying not only the bugs, but the red cells with them. In other cases, we actually have damage to red blood cells, and that damage of their outer membrane actually exposes antigens that would otherwise be hidden within the membrane of the red blood cell. It exposes these antigens to the immune system and that allows antibodies to target them and start the agglutination and destruction process.
OK, so when we're thinking about homolysis in our patients with IMHA, there are two different forms. There is extravascular and intravascular homolysis, and it's worth trying to differentiate, patients that have extravascular versus intravascular hemolysis, as it does slightly change the prognosis and potentially even the treatment plan. So extravascular homolysis is certainly the most common form of homolysis in IMHA and that's when the red blood cells are targeted, removed from the bloodstream, hence the extravascular, and destroyed in in lymphoreticular organs, like the spleen.
So this is the more common form of the disease, and these patients have slightly, less acute signs because of their hemolysis. One of the hallmarks of extravascular hemolysis to try and look for when we're differentiating these patients, is the presence of sperocytes on their smears. We'll touch on serrocytes a little bit later on in more detail, so don't worry about this too much for now.
And often as well in these patients we get quite markedly elevated bilirubin levels, so hyperbilirubinemia. Now bear in mind that not having an elevated bilirubin level does not exclude the possibility of homolysis, so just don't, don't overlook that. Intravascular hemolysis, this is certainly much less common, and it is also, unfortunately, much more acute.
So these patients have targeting and destruction of the red blood cells within the vasculature itself. And that destruction of the red blood cells releases large amounts of haemoglobin, into the bloodstream causing hemoglobinemia. So this is nicely highlighted.
And these spun capillary tubes on the right hand side of the slide. This tube here, we've got a nice normal looking plasma that's very clear. This plasma here, however, is, is very pigmented, and this is all free haemoglobin within this patient's plasma.
So this patient here, when we're spinning down their capillary tubes to perform a PCV which we're gonna do in all of these patients, it's always worth, having a little look at that plasma, to assess its colour. And if you're not running your PCVs but asking nurses or ACA to do it, just make sure that they've all been trained to have a little look at the colour of the plasma to see if it looks pigmented and whether that seems consistent with haemoglobin, if it's red, or bilirubin, if it's yellow or green. Another thing that we'll see with extravascular hemolysis on the smear are ghost cells.
So I'll show you some images of these later on. So high numbers of ghost cells on a sphere should alert the suspicion of intravascular hemolysis. So these guys, as they have a more acute form of the disease, they generally have a slightly poorer prognosis.
So just knowing which of these two categories they fall in at the point of diagnosis can be useful to help prognosticate for the clients. So now we're gonna talk about some of the putative triggers of IMHA and this is a table which highlights the many different causes of IMHA in in both dogs and cats. And this is based on information from multiple different studies looking at cases of IMHA.
And basically, grouping these guys based on the cause of their IMHA which is down here on this axis, against how strong the evidence was in those individual cases. That those triggers were actually the definitive cause of the disease. We have these nice bandings where any of these cases that fall into this first banding, there is very negligible evidence that the putative trigger actually caused the IMHA in these cases.
The next band is weak evidence, then moderate, then strong evidence, OK. So what you can see, just from glancing over this slide very briefly. Is that actually when we're looking at underlying causes of IMHA there's actually very weak to negligible to weak evidence that many of these, commonly known disorders will actually induce IMHA.
So neoplasia. Inflammation, various drugs and vaccine reactions, for instance. Actually, when you critique the information that's in the literature and it's been looked at and analysed and reviewed, the evidence that these guys actually cause IMHA is very low.
There is obviously a lot more evidence about infectious disease, so we're just gonna move on to those guys now. So in dogs, infectious causes could potentially be any infectious disease that stimulates the immune system in a way that leads to autoimmune, destruction of the red blood cells. So potentially, in theory, any infection could induce IMHA but as I say, we've got to go off what's in the evidence and the evidence most strongly supports Babezia species, OK, as a cause of IMHA in dogs.
So when we're thinking about investigating and working up our IMHA cases and ruling out, these associative causes, certainly screening for Babezia species is very sensible in any area in which Babezia is endemic, OK? We also start to think about patients, being at an increased risk of picking up infectious diseases. So those patients with a travel history to other areas, of the world that have various endemic diseases there, or any patient that, for instance, is immunocompromised, so those patients that are on chemotherapy.
Or those patients perhaps that have been splenectomized perhaps due to a trauma earlier in life. Those guys are going to be both at increased risk of infections and perhaps we might screen them a bit more aggressively for these infectious diseases. So the bees is definitely the number one.
Thereafter anaplasma species, there's definitely, enough evidence to say that those guys can, can induce IMHA and they should certainly be screened for, as well. The ways in which we can test for all these infectious diseases is certainly beyond the scope of this lecture, but generally we're looking at things like serologies and PCRs. The organisms that are then listed at the bottom here, diaphylaria, lichia, Brylia, various canine mycoplasmas, Bartanella, leishmania, Neosporin things, these bacterial infections, you know, potentially can induce IMHA, but certainly the strength of evidence is negligible, to low, based on what came out of the consensus statement that they, you know, that that they do actually, directly cause the disease.
So I suppose screening for these infectious diseases is certainly. Sensible if you're in an endemic area, there's much to know about potential comorbidities and general health status that patient, as much as anything, OK? So here again is another graph we consensus statement just looking at the various different organisms that can induce IMHA and the strength of the evidence, as to whether or not they, you know, were shown to conclusively induce IMHA in various cases.
And as you can see, . The Babezia species here, certainly there is the strongest evidence that they induce IMHA, OK, as many of these patients fall into the moderate or or sort of strong evidence category. And as you look at all these various other infectious diseases, the evidence really is, is negligible to low in these first two bandings.
Moving on to neoplasia, so certainly I was taught at university and I was told that, you know, neoplasia can induce IMHA and that we should always screen our patients for it. But interestingly, coming out the back of, the consensus statements and a critical review of the evidence. It doesn't seem that common, that neoplasia actually induces IMHA.
It certainly can be, seen in association with various neoplastic diseases, but whether or not they genuinely induce the IMHA is, is quite debatable. It's certainly worth screening patients for neoplastic disease as a comorbidity, particularly if you got an older patient, perhaps that's presented, with IMHA. But again, as this, figure on the right shows us, with all these different types of, of neoplastic diseases, the evidence is really only negligible to low that any of those actually induce IMHA, OK?
So it's something to bear in mind, that we should screen our patients for neoplasia, but don't go looking for it, expecting to find it in, in these cases, I suppose is what I'm, I'm saying. And what about other causes, I'm not going to talk about these in too much detail because there is still a lot to get through in this session. But essentially there was little to no evidence that inflammatory disease induces IMHA despite numerous case reports in the literature, when critically reviewed, again, the strength of evidence was really negligible to low.
So I wouldn't recommend screening patients for inflammatory diseases such as pancreatitis when we're looking at for underlying causes of IMHA. So drug induced IMHA is rare, or perhaps underreported and is a possible cause. So just a really thorough drug history in all of these patients is very sensible.
Just to check what new medications they've been on in perhaps the 4 to 6 weeks, prior to presentation for their IMHA . If there are any drugs that have been started, that there are concerns over, those drugs should be discontinued really immediately as part of the course whilst these patients are being investigated and treated and probably shouldn't be restarted again at any point in the future, or at least not in the near future. But as an actual cause it's really quite rare.
With regards to vaccines. I'll always ask clients when they last had their vaccine, er, in relation to when they first presented with IMHA, but actually the evidence supporting vaccines inducing IMHA is, is only low, OK. So what I tend to do is my approach is, is ask the client when they last had a vaccine, and if it was in the 4 to 6 weeks prior to presentation.
I could I could potentially put some weight on the fact that the vaccine might have something to do, with inducing IMHA in that individual, and what I would probably do is still treat them as . A regular IMHA patient with immunosuppressive therapy and perhaps avoid, you know, vaccination in that patient again, and perhaps rely on other strategies such as checking antibody teeters for various infectious diseases and trying to do their best to stay out of the way of some of those infectious diseases as humanly possible as it is. So yeah, essentially strength of evidence that vaccines are due IMHA is is low, and I wouldn't get too excited about it.
So how do we approach these guys with regards to investigation? So this is a brief summary really of, of what, what I do, and it starts off with a really thorough history, a long and a short history, I'm paying particular attention to vaccination status, travel, presence of, fleas or ticks, which could, carry vector-borne diseases, and whether or not they've been to a heartworm, endemic area. Then a thorough physical examination, and we'll go through all these in a bit more detail in a little while, followed by our clinical pathology, which will involve primarily, PCV, complete blood count or hemogram, a blood film examination by a pathologist, serum biochemistry, routine urinalysis, infectious disease screening as appropriate.
You're in culture and faecal flotation can be considered in individuals, but I certainly wouldn't class it as essential. If we're trying to save money it can easily be missed in most patients. And then some form of imaging is generally considered.
And what we tend to, you know, recommend would be thoracic radiographs and abdominal ultrasonography to screen for neoplasia. But if money really is very tight, . And then perhaps just abdominal radiography, you know, in a patient that we are, you know, I think it's highly unlikely to have neoplasia, so a young individual, would be pretty reasonable.
And that plain, lateral abdominal radiograph would be just to look for evidence, of something like zinc toxicity, which is one of the known causes of hemolytic anaemia and can really easily be screened for with plain radiographs. So certainly in our clinic, we do tend to do. Thoracic and abdominal imaging in all cases, but it's just to make sure we're excluding any of the comorbidities as much as possible and be as absolutely thorough as possible.
We very, very rarely find anything. In the way of neoplasia, for instance, that we're able, you know, to, to. Say is associated with the IMHA itself.
So which type of patients get IMHA? What's the signalment on these guys? Well, normally they're young to middle aged females or, or male mutants, with the median age of presentation being, 6 years.
We certainly have some highly overrepresented breeds for, for primary or non-associative IMHA, and I'm sure we'll have all seen a cocker spaniel or a springer spaniel at some point in our careers, with IMHA. But otherwise bichon frise, bearded collies, poodles, miniature schnauzers, miniature pincers, and, yeah, rough collies are all overrepresented for this disease. Cats are presented a little bit younger, with a median age of 2 years at presentation, and males are generally overrepresented.
What do we tend to see from our histories, when we're asking the clients, commonly we'll see lethargy and weakness because of, firstly, the anaemia, causing a state of hypoxemia, but also these patients, you know, have very, very inflammatory disorders. IMHA is, is very, very inflammatory in its nature, and that unto itself really does cause patients to feel quite weak and be lethargic, and often have a reduced appetite, so be hypoorexic. Mucous membrane pallor may well be noted by clients.
Jaundice may well be noted by clients or discoloration of the urine as our pigments are excreted in the urine. Some patients with quite fulminant or acute disease may even present collapsed at our clinics because of the severity, of their anaemia. And some patients as well, as I said, might have a reduced appetite or be completely anorexic.
And vomiting might be seen in, in some individuals as well. Physical examinations can vary between individuals, but some of the most common things that we'll see are obviously pale mucous membranes because of the, anaemia. Bear in mind that these guys often therefore will have a, a normal or a rapid capillary refill time.
As often these guys are anaemic, but have normal peripheral perfusion and not hypovolemic. So often, we should have a normal or rapid capillary refill time. If we have pale mucous membranes because of poor peripheral perfusion, because of, for instance, hypovolemic shock, often those guys will expect to have, normal or prolonged capillary refill times, that can just be helpful differentiating, differentiating anaemic patients from hypovolemic patients.
A lot of these guys are pyrexic at presentation. Because of the very inflammatory nature of the underlying disease, some of them may be jaundiced as we've mentioned, frequently tachycardic because of the level of the anaemia, tachypneic as well because of the anaemia and the inflammatory nature of the disease, and a lot of these guys can have, low grade or hemic murmurs, and that's not associated with, Primary cardiovascular disease in a lot of these guys, but actually it's just a murmur that is created in in states of quite severe anaemia because of changes in the viscosity of the blood. And these murmurs are normally low grade, 1 or 2, often systolic in nature, quite often left apical in their point of maximum intensity, and these murmurs tend to resolve.
As their anaemia resolved, so we don't get too worried or excited about those. Splenomegaly is really common in our patients and you can often quite easily palpate the spleen in an IMHA patient. So that's something that we can have a look for, and that's often just because of the role of the spleen in the destruction of red blood cells and the production of new ones.
The enlargement of the liver, may be palpable as well. In these individuals, and that's often just due to a degree of inflammation of the liver really, hypoxemic damage causing the livers to become a bit enlarged, as well as the role again in the liver in production and destruction of red blood cells. Some of these patients may present dehydrated and with some degree of hypovolemia, if they have been weak or collapsed enough to not be drinking for a while or if they have ongoing losses because of, concurrent vomiting or diarrhoea for instance.
But most patients, With IMHA, you know, at presentation are generally not dehydrated or hypovolemic, OK. So how are we gonna get to a diagnosis in these patients? Well, the diagnosis of AMHA is based on a combination of diagnostic tests, as well as response to appropriate immunosuppression.
And one thing that we have to bear in mind from the outset is that no one test is 100% sensitive or specific for the diagnosis of IMHA, which is why we need a combination of tests. So, what is the gold standard for diagnosing IMHA? Well, this is definitely one of the take home messages for today.
It is that to diagnose a patient with IMHA we really need to see two or three of the following things. So firstly, spirocytosis, which is an increase in sperocyte numbers, which is seen on a fresh blood smear. I'll show you a slide of what they look like in a second and talk about those a little bit more.
And spherocytes are really produced directly from, the immune mediated destruction of red blood cells, so we expect high numbers of those in patients with IMHA. A positive, Coons test, which again we'll touch on in a second, but that's a test for antibodies, which directly target red blood cells, and a positive, saline agglutination test. So again we'll go through that in a bit more detail, in a second, but basically any patient who has two or more of those things, you can be confident that they have IMHA, OK?
It's certainly not enough to diagnose a patient with IMHA based on, for instance, just a low PCV and an elevated bilirubin, for instance. Whilst you commonly see that in a lot of patients with IMHA, you can see that in other disorders as well, and should not be considered definitively diagnostic. Another way that we can diagnose IMHA, just off sort of a, you know, more accurately, well, more convincingly from just one test would be, the presence of positive in saline and glutination that persists after washing of red blood cells.
So we're not going to talk about about that in any more detail here, since it's kind of beyond, the scope of today and our approach in general practise. So try and remember a combination of two or more of those, three points there for making a diagnosis. So in all patients that present with anaemia, we're gonna run a PCV, OK?
Why are we gonna run a PCV? Well, yes, we have hematocrit readings on our in-house, analyzers and external analyzers, but a PCV is more accurate than a hematocrit, particularly in patients in which an agglutination is present. A PCV as well as a test that's very cheap and very rapid to run and very easy to interpret.
So anytime we run a hematocrit sorry a hemogram in our clinic, we will always perform a PCV. And when we have made a diagnosis of IMHA and we're monitoring treatment response, we always use PCV in preference to hematocrit for monitoring these patients, OK? Whenever we do do a PCV, we want to interpret it, alongside our total solids or total proteins.
And the reason for that is that obviously hydration status and, and volume status, will affect your PCV and by interpreting it in combination with the total solids, that can help you account for changes in hydration status. So we simply spin down our capillary tube, measure our PCV, snap the capillary tube, and then dab some of that plasma onto refractometer, measure the total solids on there, which is basically equivalent to protein levels. So normal PCV for a dog is 35 to 55%.
Normal PCV for a cat about 27 to 45%, OK? As I said earlier, when we spin down our capillary tubes, we should always have a check of the colour of the plasma. And, bear in mind that in our IMHA patients they normally present with a pretty marked to moderate anaemia.
So with dogs, the median PCV at presentation is 13%. Whenever we're running a PCV, and certainly whenever we're running a hemogram or a complete blood count, we should always prepare a fresh blood smear. And this is something that's easily overlooked in a busy, first opinion practise, and certainly I've been guilty of this on many occasions, but particularly in IMHA patients or any anaemic patient, we really cannot get a definitive diagnosis without making a fresh blood smear.
It is absolutely essential. So make sure you or whoever's running, Your complete blood counts or PCVs gets into the habit of performing a blood smear on every individual, make it as fresh as possible, as well. So this is obviously just prepared for a single small drop of EDTA blood.
Everyone knows how to perform them and what we tend to do is perform a blood smear in-house at our practise. We have a look at them ourselves in-house and I'll talk about what we look for in-house, but we'll always send them away, to a board of pathologist as well for them to assess an unstained smear as well. So these are some examples of some nice blood smears, that's what we're gonna aim for an unstained one on the left that's gonna go off the external lab and a diff blood smear on the right hand side that we're gonna have a look, a little look at in-house.
So what are we gonna have a look at on the smear? So we've got a patient that's we suspect has IMHA and we've done a PCV and that PCV is low. We're then gonna say, OK, we know our patient is anaemic, now let's look at a blood smear in-house to help narrow down our causes of anaemia.
So when we're looking at anaemia patients, we've got two nice broad categories that we can group them into patients with regenerative anemias, and if you have a regenerative anaemia, you essentially either have IMHA or haemorrhage. And then patients who have non-regenerative anemias. So there's a long list of causes of non-regenerative anemias that involve systemic diseases, primary bone marrow diseases, etc.
Etc. . And one thing to sort of bear in mind is that as with anything in internal medicine, patients never read the textbooks, and we have to be aware that up to 30% of dogs with IMHA actually can have a non-regenerative anaemia at presentation.
And in those individuals, it's often because the IMHA. In some degree or fully is actually not only targeting, circulating red blood cells, but actually targeting immature red blood cells in the bone marrow as well. So those patients who have non-regenerative IMHA's again are a bit beyond the scope of today, but they're the guys that we end up needing to perform bone marrow aspirates and core biopsies on to get a definitive diagnosis in those guys.
So those are often patients that end up getting referred, you know, for evaluations. So we want to do our smear analysis, as freshly as possible, because it certainly, can affect, the interpretation of sperocyte numbers, and we definitely want to do our, smears as well prior to giving any stored blood products as well, because again that can hinder interpretation, of the smear. So we're gonna look at the smear and we're going to try to say, is this anaemia regenerative and therefore IMHA or blood loss, or is it non-regenerative, which means a much longer list of causes and and lots of, you know, further tests.
So how are we gonna do that? Well, we're gonna look for evidence of anisocytosis, polychromasia and reticular cytosis. So these things tell us on a blood smear that our patient has a regenerative anaemia, OK?
And, And anisocytosis is a variance in red blood cell size, OK. And when you look at a blood smear, you'll see a difference in the overall size of all the different red blood cells, and it's because these are not fully mature red blood cells, but a mix of mature red cells and more juvenile red blood cells which have just been released from the bone marrow in response to blood loss or hemolysis in these patients. So I'll show you that in the next slide.
Polychromasia is something we're gonna look for which is a variance in colour or hue of the red blood cells, again, because we're looking at a sort of a mix or a melange of different red blood cells. Of different levels of maturity, and we certainly see that the more juvenile red blood cells often have a more blue or basophilic colour or hue to those cells. Reticulocytes are something that we can count on, on some, you know, in-house analyzers, when you're performing, a hemogram, but they're also something we can look for on a smear.
If we stain it up with a new methylene blue stain, we can actually perform a manual reticulocyte count. So what does anisocytosis look like? Well, here's a good example.
So we are looking at a smear of an anaemic patient, and the first question we ask ourselves is, is there variation in red blood cell size, i.e., can we see anisocytosis?
And as we look at this patient's smear here. We can clearly see that this red blood cell is not the same size as this one here, OK? This red blood cell here is not the same size as this one here.
There is clear variance in size. There is anisocytosis. So already we've got an indicator that this patient has a degree of regeneration.
If you're at all unsure. About variance in size on a blood smear, one of the things I tend to do is try and find the biggest cell on that, high powered field, and then the smallest cell, and this is at 100 times magnification on oil immersion. And I'll compare the smallest red blood cell on, on that, field with the largest one, and you know, if I can see really any substantial difference in size, that patient probably has a misocytosis.
So this is definitely something which should be performed in first opinion practise by GPs, and or nurses, for helping us assess for regeneration, and very much the same with polychromasia as well. So this patient, as you can see, does have a bit of a variation in red blood cell size, but also there's a clear variance in red blood cell colour or hue, with some of these more juvenile red blood cells being a lot more blue or basophilic in their appearance, with the more mature red blood cells being a bit more red in their appearance. So again, This patient smear, we can look at it and quite clearly say, yes, there is some variance in the colour of these red blood cells.
This patient has polychromasia, this patient probably has a regenerative anaemia. It really is not rocket science. Patients with non-regenerative anemias.
OK, that do not have any anisocytosis or any polychromasia. All their red blood cells look identical, OK, exactly the same size, exactly the same colour. So we call that normocytic, normochromic, OK, and those guys often really are.
Quite easy to differentiate from patients with strongly regenerative anemias such as those that we see in IMHA. Spherocytes, so we look for these guys again on, 100 times high power, magnification, and we'll find these, cells in the monolayer of the smear. And these spherocytes are produced, basically, in cases of red blood cell, destruction.
Which could be due, you know, to, other causes as well as IMHA such as oxidative damage because of zinc toxicity, as I mentioned earlier, paracetamol toxicity, and venomation from a snake bite, PK deficiency, which is a congenital problem found in certain breeds of dog, or due to any disorder that, gives you more fragile red blood cells. And essentially. These spherocytes are very small and round red blood cells, so they've lost their biconcave disc shape, which is the normal shape of red blood cell, and that's occurred because essentially their membrane has been damaged by attack from the immune system or from direct damage.
From secondary causes, and that damage to the red cell membrane causes it to just lose its regular shape, it's biconca disc shape. So these become smaller, more spherical, red blood cells. So we can actually have a look through, spherocytes on a smear, and count the number of them per high power or oil oil immersion field.
And if we see more than 5 spherocytes, Per high powered field, that gives us about a 63% sensitivity and 95% specificity for the diagnosis of IMHA. So here's an example again of some spherocytes on a smear. So what you can see is these guys are smaller than the other red blood cells, and they've lost their bi concave disc shape, so they don't have that area of central pallor.
So if you see lots of these guys on a smear, they're probably spherocytes, that patient probably has IMHA, OK? If you're unsure about any of these things, don't worry, we've already said that we're gonna submit a fresh smear to the external lab for a boarded pathologist to have a look at it for us. But it's really nice to be able to have a look at a smear yourself in-house and confidently say this patient.
Has a regenerative anaemia, I believe it has IMHA. I'm going to institute treatment right now, life saving treatment for this patient, and then you get your report back 24 hours from the external, later from the 20 from the external lab, and they confirm your findings, OK? So these are things that are really try and recommend that people get practising at you know, in their clinics, OK, having a good look at fresh blood smears, in, in all patients, but particularly those with anemias.
So we've had a look at our PCV and blood smear and then we're now gonna move on to in saline agglutination test. So any patient that I'm suspicious of IMHA I'll perform a saline agglutination test on, again is one of the criteria for diagnosis of IMHA and the technique, . Of choice really is to mix 4 drops of room temperature saline with 1 drop of EDTA blood.
We then rock the slide back and forth for a minute, and we have a look at the slide with our naked eyes for evidence of macro agglutination or visible clumping of red blood cells, which I'll show you on the next slide. We then have a little look at the slide under the microscope. On the 40, lens to have a look for microscopic auto agglutination because there are a number of patients that will not have macroscopic agglutination when we, just visualise their smear, but actually when you get it under the microscope, we'll have evidence of microagglutination.
And just by popping these smears, sorry, these slides under the microscope, it can just help us increase our sensitivity when we're, you know, screening for IMHA. Bear in mind that macro glutination has a 100% specificity. So if you see, you know, a marked a glutination on an insullo test, you can be pretty confident that patient, you know, has IMHA.
It does unfortunately they have a low, sensitivity. The sensitivity is in the order of about 30%, so only about 30% of our IMHA patients, you know, will have, In saline and glutination positive tests, so a negative one does not exclude IMHA. So, the image on the right, just shows you here a patient with macro agglutination, OK, confirming, you know, a diagnosis of IMHA.
Whereas here, this is a patient who does not have evidence of macro glutination. They could, however, have microglutination, so this, patient we would then have a look at that blood, underneath the microscope. So that's just one drop of EDTA blood mixed with 4 drops of warm saline.
OK? And this is how micro glutination tends to appear, . When, assessed under the microscope.
So we see, 3 are red blood cells, which is kind of normal when they're sat in saline, but then we have lots of clumps here of red blood cells, all sat one on top of each other, OK? So these are aggregates of micro glutination. OK, so we're gonna now start to move on to other tests that we're gonna use to help support our diagnosis of IMHA and screen for sort of comorbid disease.
One of the things that we quite commonly see is thrombocytopenia. So when we get thrombocytopenia in patients with IMHA, it's important to be aware of because it does sort of change how we manage those patients, you know, physically and from a nursing point of view, we have to bear in mind that we don't want to take, you know, central, blood samples, for instance, if you've got a thrombocytopenia, . But it does also actually affect the prognosis.
The concurrent thrombocytopenia in an IMHA patient is a negative prognostic indicator. So that's important to be aware of. We see, thrombocytopenia in our IMHA patients for a variety of reasons.
It could be that our patient has, concurrent DIC, which is really quite common. In IMHA patients and they may not have external signs of a coagulopathy, but it might just be a bit more of a low grade DIC where platelets are being consumed because of the very severely inflammatory nature of the disease. It might be that our patient actually also has, targeted platelet destruction from the immune system, so IMTP, mated thrombocytopenia, in combination with IMHA, and we refer to that as Evans syndrome.
When we see platelet counts in IMHA patients getting below 30 and certainly below 10, that would really, Trigger alarm bells in my head that we've got a concurrent IMTP. When we've got platelet counts above sort of 30 or 50 times 10 to 9 per litre, are we a bit more suspicious that actually those platelets are being used because of DIC or splenic sequestration rather than there being a concurrent IMTP. We'll run our platelet counts on hemogram, but also I always recommend doing manual platelet counts as well on a blood smear.
That's beyond the scope of today's lecture, but again, something I'd recommend everybody in general practise or otherwise gets into the habit of performing. We often see stress leukograms or evidence of inflammation in our patients with MHA so often a neutrophilia and a monocytosis, we may even see a degree of lympopenia or earinopenia. So moving on to the Coombs test.
As I said earlier, this is a, test for, antibodies directly targeting, the erythrocytes, and this is something that will run at the external lab. And this test isn't too bad actually, in helping support the diagnosis of IMHA, with a sensitivity of 60 to 80% reported in dogs, about 80% in cats, and it's pretty good specificity in both dogs and cats, of about 95 to 100%. So again, any patient that I'm suspicious has IMHA I'll pretty much always submit a Coombs test to the external lab for testing.
Couple of important things to be aware of. We want to submit this sample to the lab prior to any immunosuppressive therapy, because it is possible that if we start immunosuppressive therapy and that patient's been receiving it for long enough, that could switch off, . The Cooms test to give us a false negative if you will, on our Coombs test.
So basically try and perform the Cooms prior to immunosuppressive therapy. If that patient has been on immunosuppressive therapy, if they've only been on it for sort of a few days, you know, and still have really active evidence of homolysis, then they almost certainly will still have a positive Coombs test, so you know, don't, don't get too panicked if they've been on Preds or. You know, dexamethasone for just a couple of days, .
We also want to try and collect our Coombs test prior to blood transfusions as well, because it is possible that blood transfusions could interfere with Coom's test also. Finally, a few of the things that will support a diagnosis of IMHA. We said at the beginning, hyperbilirubinemia, common in our patients.
Hemoglobinemia, common in those with the intravascular hemolysis, and obviously therefore hemoglobinuria. And also I mentioned those ghost cells as well on a fresh blood smear, so it's got to be fresh. And it has to be on a, again, a blood smear of a patient who has not had not received a blood transfusion already.
But essentially, ghost cells are red blood cells that are very, very faint in their appearance, as you can see on this image here, and seeing the presence of those would certainly support a diagnosis of IMHA and particularly, a degree of intravascular hemolysis in that individual. Hyperbilirubinemia is also, has also been identified as a poor prognostic indicator, so always make a note of that when you see it. When we perform biochemistry and urinalysis in our patients, we really quite commonly, detect elevated, liver enzyme activity, so ALP and ALT.
The magnitude of their elevations can be quite marked in some individuals, but most it's often mild to moderate, and that's often not because of, You know, a concurrent, hepatopathy or a hepatopathy that's inducing IMHA, but it is often just hypoxemic damage to the liver, because of, the anaemic status of that patient. And what often happens is we treat our patient with immunosuppressive therapy, normalise, . The PCV and often these enzyme elevations, you know, return to normal and really often don't require any further investigation or supportive therapy, in my opinion with hepatorotectants unless they really are quite markedly elevated liver enzymes, OK?
We might see elevated urea in our OHA patients and when we do, that's certainly been identified quite, a few times in various studies as being again another poor prognostic indicator, so a good one and to look out for. So what about treatment, OK? So things to bear in mind with treatment are that it's not always successful.
So we need to do as much as we can as early as we can to really optimise therapy in these individuals. I think we need to bear in mind that we initiate therapy as soon as possible, once we have made a diagnosis and or collected all the diagnostic samples, you know, that we need to make a diagnosis, which I've already talked about, over the last few slides. Essentially, the cornerstone of treatment of these patients is immunosuppressive therapy.
So we certainly have to be confident of our diagnosis, you know, before starting immunosuppressive therapy, because if we start immunosuppressive therapy in a patient that has anaemia, for instance, because of, you know, a primary infectious disease rather than a primary IMHA we could worsen, that patient's anaemia, OK? And if they have an anaemia because of some other reasons, such as blood loss, obviously immunosuppressive therapy that would be detrimental in those individuals. And I suppose a a brief, thing just to mention at this point, really is that when we are talking about the immunosuppressive therapy from this point on, it really is for patients with primary, or non-associative IMHA and not for those patients with secondary IMHA due to infectious diseases.
Essentially, if you have an IMHA that's due to an infectious disease, you mostly just treat that infectious disease with an appropriate. You know, antibiotic or, or whatever therapy it is, and clear that organism, and that should resolve the IMHA in most cases, of, IMHA caused by infectious diseases, such as Babezia species, we don't need concurrent immunosuppressive therapy because that could actually, make, the underlying infection worse and further worse in our IMHA. There are always exceptions to the rules, don't get me wrong, but as a, as a broad rule of thumb, that's the way we tend to go.
Bear in mind as well that if we're starting things like prednisolone as part of our immunosuppressive the therapy, that could actually mask the diagnosis of some underlying diseases, such as lymphoma. Although, as we have said earlier, the strength of evidence that neoplastic diseases like lymphoma, of course MHA is actually quite low, but it's just something to bear in mind. And as I've said earlier as well, transfusions, may also affect the results of, things like our complete blood count and smear analysis.
So transfusions, I'm really not going to talk about this in any significant detail, because again it's way beyond the scope of this session. But essentially, if we're going to consider a blood transfusion, we'll probably do it in patients that have a very low PCV, so often in those with a PCV below 15, in, in dogs, and patients that also are not coping with that PCV. So I've certainly had patients who've come into the clinic, you know, With normal heart rates, normal respiratory rates, ambulating just fine, eating just fine, with a PCV of 15.
Am I gonna push that patient for a transfusion? Not really, no. If I however have a patient with a PCV of 15 that's presented collapsed with a heart rate of 160 beats per minute, you know, that patient I probably will push for a blood transfusion, so just.
Think about not only the numbers but also the patient's clinical state when we're trying to decide, do our patients need a transfusion or not. Any patient that we're going to transfuse, we should always blood type them first. So that we can give them, you know, the most appropriate blood, and if that patient has had, a blood transfusion, previously, certainly, more than, 5 days prior to this transfusion, cause it takes your body about, 5 days to produce.
Antibodies against, other the blood groups. So if you've had a transfusion more than 5 days prior to the one you're about to receive, you should also be, crossmatched as well. And, and there's some really nice, in-house crossmatching kits that are available now, you know, that can make that process.
It's very, very easy. Again, way beyond the scope of today to talk about this in any, more detail. But essentially if we're gonna transfuse our IMHA patients, the best type of blood that we can give them are packed red blood cells in preference to whole blood transfusions, and that's because essentially they're double the concentration.
So for the same volume of blood transfused, we're giving twice the number of red cells, and that's really useful in our IMHA patients because as we said at the beginning, a lot of these guys present nor volemic, but with an anaemia. So they just need as many red cells as they can in as little fluid as possible. So I've already talked really through, you know, assessing the severity of the patient's at IMHA and the need, you know, for, for transfusions.
But, certainly a good, take home fact and something that was highlighted in the, the recent consensus statement is that there is evidence that actually, transfusion reactions and mortality rates in IMHA patients are higher in patients that receive. Packed red blood cell transfusions, of bags of blood that are more than 7 to 10 days old. So essentially if you have stored blood in your clinic or you're ordering in stored blood for, for, for instance, the pet blood bank, just try and ask to get, a unit of blood.
That was collected in the last 7 to 10 days if your patient has IMHA. If it has some other form of anaemia, I don't believe there is any evidence to say it has to be fresh blood, so maybe use older blood for other forms of anaemia and fresher blood for our IMHA patients. And there is also no current recommendation for the use of fresh frozen plasma in IMHA patients as it has not been shown, to improve outcomes.
That's something that we don't really need to consider using the most. So what about immunosuppressive therapy? Well, good old prednisolone or vitamin P as I like to call him, is really the cornerstone of treatment, as it is in, in many of our, you know, autoimmune diseases.
And I'm sure everybody will be aware of this. But I suppose the important things to highlight are that really the dose of prednisolone has to be appropriate. So if you are giving less than 2 milligrammes per kilogramme per day, you're really not at an immunosuppressive, dose.
So when we initiate therapy, it has to be above 2 milligrammes per kilogramme per day. And we really don't want to go too much above that. So we tend to recommend an initial dose range of 2 to 3 migs per gig per day.
If you go over that dose range, yeah, absolutely you're given an immunosuppressive dose, but there is a lot of evidence in humans and, and, and to a lesser degree in animals, that as we go over 2 mix per keep per day, we actually don't get any additional immunosuppressive benefits, but actually do significantly increase the side effect profile of prednisolone. So really, I tend to get them on 2 to 3 gigs per gig per day, you know, from, from the outset, of therapy and really no higher and no lower than that. Because of the horrendous side effect profile of prednisolone, you know, when it's used at these dosages, chronically, what I often do is use a slightly lower dosage in large breed dogs because larger breed dogs are much more susceptible to the side effects of prednisolone.
And those side effects, obviously PUPD is a really common one, could be frustrating for the clients, but in large breed dogs, the degree of muscle atrophy and skeletal muscle weakness can be really, really profound. You know, and I've certainly had clients that have toyed with the idea of euthanizing their dog, so. Large breed dog because of its long term, you know, steroid side effects.
So in large breed dogs, what we tend to do is work out a dose based on their body surface area. So 50 to 60 milligrammes per metre square per day in dogs that are over 25 kg and below 25 kgs, 2 to 3 migs per kid per day would be fine. I tend to initiate prednisolone as the drug of choice in all my AJ patients.
If they're too poorly, however, to tolerate oral medication, I'll use dexamethasone in preference, at 0.2 to 0.4 migs per gig per day, but there is certainly no, proven benefit of using dexamethasone.
So start them on Dex and then move them onto prednisolone or just start them on prednisolone from the word go, whatever works really. We have an initial response rate of about 80% in patients that are receiving, prednisolone, and those that do respond, we keep them on that dose, for about 1 to 2 weeks. And then if we have, a stabilised PCV or an increasing PCB which we'll touch on in a few more slides, then we start to decrease the dose at that point, and we'll just drop them to just under, 2 weeks per gig per day, you know, within 1 to 2 weeks of starting therapy if they are showing a positive response.
So prednisolone, pretty straightforward as everyone use it, everyone's using it, what about additional immunosuppressive therapy? Well, this is something that I do use really quite frequently, but it's based on certain criteria that I think about in each of my patients. So there is no survival benefit that has been shown, OK, when looking at studies of adding in a second immunosuppressive therapy from the point of diagnosis versus just prednisolone on its own.
OK? So we're not using these drugs. Because of clear improvements in outcome in in individuals.
But the reason really why we're using it, is either because patients are essentially not responding to the prednisolone, on their own, which some patients, you know, do fall into that category, or. We have a patient that essentially is at a significant risk of steroid side effects in the long term. So for instance, patients who have had previous pancreatitis, or as I said in the last slide, patients that are over 25 kilogrammes, you know, these patients.
I worry about them being on high doses of prednisolone long term, and I tend to add in a second immunosuppressive therapy from diagnosis, so that I can reduce that dose of prednisolone a little bit more quickly because I've got a second immunosuppressive drug sat there in the background, helping with immunosuppression. So essentially, the recommendations for starting an immunosuppressive therapy would be if a patient initially presents with severe. Or life threatening disease, OK, if a patient has had an over 5% decrease in PCV every 24 hours during the first week of prednisolone treatment.
In any patient that has persistent agglutination after 7 days of prednisolone treatment. Or in any patient, that is transfusion dependent after 7 days of prednisolone treatment, OK. So any of those, factors for me would say this patient is going to benefit from an immunosuppressive, a second, sorry, immunosuppressive therapy, or if, as I say, they're a dog that's over 25 kg, we're worried about using prednisolone because of pancreatitis previously, OK?
So we've said that quite a few patients can benefit from an additional immunosuppressive therapy. What are our options? Well, it's generally either azathioprine, cyclosporin or mycophenolate Moffatil.
Now there's no evidence in the literature to say that any one of these drugs is better than the other. There are some studies that show weak evidence that one drug outperformed another, but on a critical review of the data, really any of these drugs are appropriate. Just bear in mind, when we selecting these drugs, we have to think about duration, of onset, side effect profile, costs, you know, to, to try and, you know, decide which of these drugs is most appropriate.
So azathioprine, we tend to use it 2 migs per gig, once daily, or 50 mg per metre squared once daily. This drug takes a good 2 to 4 weeks, to really have its full effect, . And it's, you know, side effect profile, is generally, things like, well, we'll touch in the next slide actually, but it's nice and cheap, which is great, which makes it a very affordable option, for clients, you know, and it is easy, to administer and generally well tolerated when even orally, cyclosporin.
Is, licenced in the UK as atopica. We give that at 5 migs per gig twice a day, so bear in mind that's double the frequency, that atopica is licenced for for atopic dermatitis. So this drug is, you know, slightly more, rapid in its onset of action than azathioprine, perhaps, you know, 1 to 2 weeks to have its full effect, .
Although this drug is eye-wateringly expensive, so you have to bear that in mind when we're thinking about having patients on this for 6 to 8 months, can our clients afford it? And certainly in the short term when we administer cyclosporin to patients, it can cause vomiting and diarrhoea. So two ways around that are to actually freeze the cyclosporin capsules because they've been shown.
Be just as effective when frozen, but actually have less GI side effects. Or for the 1st 5 to 7 days of treatment, we can administer cyclosporin with a meal. That just helps again reduce GI side effects, and then after the 1st 5 to 7 days, we tend to give cyclosporin on an empty stomach because it increases the bioavailability of the drug.
Mycophenolate Moffattil is something, that we can consider because it's probably the fastest in its onset of action. And, you know, we can give this orally, twice daily, to our patients. The one significant downside of this drug is that, it can cause quite severe GI side effects, vomiting and diarrhoea, in particular in, in the first few days of treatment.
That was reported quite a lot, when it was originally used at 20 migs per gig twice a day in a couple of studies. We now recommend lower, dose rates of more like 10 mg per gig, twice a day with mycophenolate. Not particularly an expensive drug either, so it's quite a nice one to consider using.
What about human intravenous immunoglobulin? As we're running out of time and, you know, there really, it's not a lot of sort of to say about it. I think I'm gonna briefly say that it is eye-wateringly expensive and in the UK certainly at least at the moment, almost impossible to get hold of at the moment.
So the recommendations for this drug are that if you fail to respond to prednisolone and an additional immunosuppressive therapy, then this is probably the next treatment that we should look at using. As I say, a single bolus of this drug, can be used to treat IMHA, but it really is very expensive and very, very hard to get hold of, so I'm not gonna talk about it any more than that. This is a nice flow diagram again, from the, ACIM consensus statement on the treatment of IMHA, and it's just a really nice one to have to hand to help you work through, your patients who've got IMHA about whether we start prednisolone, and a second immunosuppressive drug or just prednisolone on its own and what to do from there if they're not responding.
Just gonna briefly talk about hypercoagulability. Our patients with IMHA are at significant risk of thrombosis, and, there's been some studies that have looked at PMs on these patients, and have found that up to really 100% of these patients have some degree of thrombosis, at postmortem. And it's often the thrombosis that can kill these patients.
I've certainly lost quite a few IMHA patients to thromboembolic disease, OK? Most commonly pulmonary thromboembolisms causing dyspnea. The recommendations, for the treatment of, of hypercoagulability, which is, really commonly seen in our IMHA patients because of the very, very inflammatory nature of the disease, is to, treat them, treat them with, therapy that targets, the coagulation factors, which we'll talk about the next slide, and also therapy that targets, the platelets, which is on this slide.
So basically we're gonna start all of our IMHA patients on an antiplatelet drug from the word go and keep them on that the entire time that they are on prednisolone, OK? And that's because prednisolone also increases the risk of thrombosis. So we're gonna start patients on an antiplatelet drug from the word go, if they have a platelet count above 30.
If their platelet count is below 30 times 10 to 9 at diagnosis, we would, withhold antiplatelet drugs and those guys, cos we could. Increase the risk of, you know, coag a lot of bleeding out. And the coagulopathy.
. But otherwise, we tend to recommend starting clopidogrel as the anti platelet drug of choice in preference to aspirin, at a dosage of 2 to 4 mg per gig once daily by mouth. So that either comes in . This form, which is Plavix, 75 milligramme coated tablets, or you can get smaller tablets at 18.75 milligramme from compounding pharmacies such as Summit Pharmaceuticals in the UK.
So we tend to start clopidogrel in all of our IMHA patients and keep them on that until they discontinue their prednisolone therapy. Anticoagulants can be considered in the first two weeks of therapy, . That target the clotting factors, and these drugs are generally heparin in the form of low molecular weight heparins or fractionated heparins.
I'm not gonna really talk about them any more than that at this point, because I think we're talking about treatment of IMHA in, in, in first in general practise, and the use of these drugs in that setting is, is, is quite hard to sort of titrate those to effect. Fab. So we're pretty much wrapping up now.
What do we do once we've started our immunosuppressive therapy in these patients? How do we monitor them? Well, we're gonna monitor primarily PCV and if our PCV is stable and more than 30% for two weeks with improvements in the other indicators of homolysis, .
Then we're often able to decrease our prednisolone dose at that point, by 25% if it's the single agent being used, or about 25 to 50% if there are two agents being used, OK. So do note there that what we classify as an appropriate PCV to start to lower our doses of immunosuppressive therapy is not a normal PCV but a PCV of over 30. So once your PCVs are getting above 30, patients are responding, you can start to decrease and dosages, OK?
Thereafter, we tend to decrease the, prednisolone dose by 25% every 3 weeks long term if their PCV remains above 30%, or if we are on two immunosuppressive agents, we can decrease the dose of prednisolone by 25 to 33% every 3 weeks, or 25% every 2 weeks long term. So, we start patients on high doses of immunosuppressive therapy, and we start to down titrate the dosages approximately every 2 to 3 weeks, well long term. We tend to reduce the dose of prednisolone first, and the reason for that is, as I've said, prednisolone tends to by far have the most severe long term side effects when compared to the other immunosuppressive agents.
So we try to get patients off their prednisolone first. And that takes about 3 to 6 months of steady down titration to get them off of that drug. Once we have, tapered our patients off of prednisolone and they've maintained, a normal, PCV, we then, either have the option of continuing the second immunosuppressive drug for 4 to 8 weeks at the same dose as that we started it on.
And then discontinuing it altogether, 4 to 8 weeks after the prednisolone, or after stopping the prednisolone, we have the option of slowly down titrating, the dose of the second immunosuppressive agent. So essentially there's no clear evidence in the literature to say which of those two ways is the best of doing it. Personally, I downrate the predriolone, stop that, and then down titrate the dose of the second immunosuppressive agent rather than stopping it just altogether after 4 to 8 weeks, just because I feel a bit more comfortable if that patient relapses, it isn't in any way, shape or form associated with suddenly stopping a drug rather and then down titrating it.
So what this means for our IMHA patients is that they are generally on immunosuppressive therapy for a good 6 to 8 months, OK? They're often on prednisolone, for about 4 to 6 months, but all immunosuppressive therapy for a good 6 to 8 months. And certainly one of the number one causes of patients relapsing with IMHA is because patients have their immunosuppressive therapy stopped too early or tapered down too quickly.
So don't fall into that trap of, of down titrating doses too quickly. You know, this is quite a long treatment course. With regards to other monitoring of these patients, whilst you're on long-term prednisolone, it's ideal to culture urine every 8 to 12 weeks and check a sediment to see if they've got evidence, of, you know, urinary tract infections, because of the increased risk of UTIs in patients on long-term prednisolone.
We have to bear in mind that azathioprine long term, whilst generally well tolerated, it can itself cause a degree of myelosuppression. So we tend to check a CBC at the 2 week mark. And then every sort of two months, long term, just to check that we're not actually causing any suppression of the bone marrow with our azathioprine.
And we also tend to check biochemistry as well intermittently, just because azathioprine can induce hepatotoxicity in, in a small number of patients, OK? Cyclosporin generally is very well tolerated long term. Other than causing sort of, unusual varicose lesions of the, gums in, in the mouth.
It's generally very well tolerated. Ideally though, we should probably take a biochemistry every 2 to 3 months long term because it can cause, hepatotoxicity in, in a small number of patients. If we're on long term mycophenolate, .
We tend to check a complete blood count every 2 to 3 weeks when monitoring these guys, during the first month or so of treatment, and then every 2 to 3 months thereafter. And again, because mycophenolate, can cause a degree of, myelosuppression itself. And when we see myelosuppression with, azathioprine and mycophenolate, it can cause, you know, potentially quite severe myelosuppression, but normally it's quite mild to moderate.
And one thing to bear in mind is that if you have that patient that is on long term azathioprine or mycophenolate, and you're just struggling to get those PCVs, you know, up into the sort of mid to high 30s, you know, they're just hovering with a low normal or just slightly low PCV. It might actually well be because you have some mild, myelosuppressive effects of the azathioprine or mycophenolate. And in those individuals, you know, if I was in any doubt, about the degree of myelosuppression, I would probably look at dropping the dose of the azathioprine or mycophenolate, you know, before, tapering off the prednisolone altogether just to help, you know, reduce any myelosuppressive effects of those drugs.
Supportive therapy, this is often something that, that, that we get asked about, essentially, there's very little supportive therapy needed for these patients when they get sent home. Most of supportive therapy is required whilst they're in hospital. So if they, already have GI ulceration, or known risks of ulceration, then I'd start them on gastroprotectants with generally proton pump inhibitors such as omeprazole.
During high risk periods. So generally, when my patient is in hospital, really sick with bad IMHA, anorexic or hyperorexic, and no immunosuppressives, yes, I'll probably put them on a PPI, but once that patient is well, coping with their, level of anaemia and eating, I'll discontinue, . Omeprazole, and I certainly will not send patients home on long-term omeprazole, with IMHA, you know, prednisolone.
I think there is absolutely no evidence, that it would be of benefit, and there are potential, you know, long-term complications of chronic, . Omeprazole therapy. Oxygen supplementation obviously we're gonna consider in any patients clinically unstable whilst in clinic, and fluid therapy, as I mentioned earlier, is often unnecessary in our IMHA patients, as most of those patients present norvolemic, not dehydrated, and therefore, you know, don't require fluids, particularly if they're eating and drinking by themselves and don't have ongoing losses through vomiting and diarrhoea.
And be aware as well that even actually having a catheter in situ in some of these patients might not be necessary. You know, if you're not giving any drugs intravenously because they're on oral prednisolone, oral azathioprine, oral clopidogrel, you know, do they need an IV? Because one of the, sites that thrombosis can start to occur is on the end of an IV catheter.
So we can actually give our patient a thromboembolic event from having a catheter in situ in that individual. So I try and get my IV catheters out of my IMHA patients as quickly as possible. We have to consider nutrition, in our individuals, so assisted denial nutrition if they're unable to eat for themselves.
Hygiene is very important, as we're immunosuppressing them, and also, being aware that, some of these guys are thrombocytopenic, and that therefore we have to be careful about how we handle them and how we blood sample them. So final slide you'll be glad to hear, just to touch on prognosis, mortality rates vary dramatically from one study to the next, and have been reported to be in the, in the range of 20 to about 80%, . But generally, you know, most patients, I would say it's a broad rule of thumb, certainly in my experience is that about a third of patients don't tend to make it out of the hospital in my experience, with the most severe forms of IOHA and the other 2/3 generally tend to make it home and do reasonably well.
And those patients that do succumb to disease, as I said, it's often due to thromboembolic events. Because of their massively increased, risk of, thrombobolic disease because of their hypercoagulable state. And if that's going to happen, it generally is most likely to happen in the 1st 2 to 3 weeks.
So again, I often say to clients, once you're out of the hospital and you're home, you know, for a good couple of weeks, you're probably in the clear, and that, you know, mortality seems to be, much less of a problem. Relapse obviously is something that can occur and can occur at any point, and it may even be that, relapse can occur in an individual several years after, discontinuing their therapy, but generally relapse rates are reported to be in the order of about 10, 15%. So it's just something that's important to bear in mind when we're, making clients aware of the, the longer term prognosis.
And as I said already, those patients that do succumb to disease generally do so because of thromboembolic disease, or, or something, like DIC or potentially sepsis in those patients that are severely, you know, immunosuppressed from their immunosuppressive therapy. So that's all from me. I hope you've enjoyed that.
I hope you've found it relevant to what you're doing in general practise, and I hope there's a few sort of top tips, you can take away from that, that you can put into practise, you know, as soon as possible, when you're next seeing your anaemic patients. So, thanks everybody for listening and I wish you all a very merry Christmas. Take care, bye bye.