Hello guys, welcome to this webinar on the emergency management of immune-mediated thrombocytopenia. So this is gonna be a whistle stop tour of everything that we need to know in primary care practise to be able to diagnose and treat these patients successfully. So we're going to start off with an overview of coagulation.
We have to understand the normal clotting cascade to be able to understand when things go wrong. And we'll then discuss the different causes of thrombocytopenia because there are other differentials that we have to be aware of other than just ITP. Then specifically how we diagnose ITP itself and then at the end, the treatment of ITP focusing on those patients that are hospitalised with the more severe forms of disease and then how we, monitor and treat these patients as outpatients.
So to start out, we're obviously interested in platelets, and it's important to know that platelets obviously are essential in coagulation. They play a very fundamental role in primary coagulation, which is essentially the way that the platelets interact with damaged vascular endothelium to really start clot formation. Platelets themselves are produced in the bone marrow.
And they're produced as fragments of larger, more juvenile platelet precursors called megacarriocytes. These megacarrier cyte numbers increase when there is peripheral consumption of platelets, and we need to produce new platelets. These mega carrier scytes are found generally in the, in the bone marrow but can be found in the bloodstream as well.
Platelets. Have a very short lifespan of only 5 to 7 days. And as we'll get onto in a few slides of time, their numbers can significantly decrease in lots of different, sort of disease states.
So when we're thinking about normal coagulation, I think the best way to approach it is the cell-based model of coagulation. So this is sort of the current theory on how coagulation occurs in vivo, and there's 4 main steps to it. So the initiation step, the amplification step, propagation, and termination step, and this is the way that we sort of think about clot formation.
Stabilisation and ultimately then clot breakdown. And it's quite a complicated, sort of model to know inside and out, but fortunately, with respect to sort of, platelets and their role, their role very much is in the first step, of the cell-based model, which is initiation. So essentially what happens, and I'll show you in the next slide in diagram format, is that we get damage to the vascular endothelium, and this exposes tissue factor and von Willebrand's factor to the circulatory system, so they should normally be sort of protected, hidden if you will, from the bloodstream by the vascular endothelium, but when it's damaged because of a trauma.
They become exposed, and ultimately it's the von Willebrand factor that allows platelets, to start to bind to the vascular endothelium. Once they're bound to the endothelium, and starting to form a platelet plug, we then get sort of activation of various different clotting factors, on the surface of the platelets. To start to form the fibrin mesh, which we think of really as a secondary coagulation.
So the diagram here sort of summarises that, essentially what we have. I just pull up a pointer, is this, I mean it's very much a schematic diagram that just knocked together in about 10 minutes, but ultimately we get damage to the endothelium, and that exposes von Willebrandt's factor which allows platelets to bind to it. And we also get exposure of this tissue factor, which sets off.
The clotting cascade and ultimately, during the sort of initiation and amplification stages of the cell-based model, we get factor 10A converting prothrombin or factor 2 into thrombin, which is able to bind to the platelet plug, and then various other clotting factors are able to bind to thrombin. And so the sort of clotting cascade continues. So ultimately, you know, we can think about this cell-based model and how important platelets are in it, and then obviously if we have decreased number of platelets, we're going to have abnormal coagulation, or if we have platelets that are not functioning as normal, then of course we're also going to have abnormal coagulation as well.
So we're specifically talking about thrombocytopenia and the different causes, and it's important to be aware of what they all are. So broadly speaking, we can break these down into the inherited and acquired causes, and within the inherited causes, there's a few different breeds that we need to think about. So for instance, Cavalier King Charles Spaniels, .
Have inherited macrothrombocytopenia, so they have these really large platelets, but less of them than other breeds of dog. And if you run a CBC on these patients, often the number of platelets comes out reduced below reference interval. But actually these platelets, whilst reduced in number are much bigger ones than most nor most other breeds.
And as a result, their total platelet mass is normal and they therefore don't have any problems with their clotting. But it's something to sort of be aware of in the breed. We also have sighthounds as well, so they, for instance, have lower platelet counts than most other breeds.
So we just need to sort of be aware of some of the different inherited thrombocytopenias that we can see. But ultimately, we're going to be more interested in the acquired causes, and of which we've got a few to be aware of. Firstly, we've got artefact.
So that is when we have essentially, sort of sampling technique and or machine error, that causes a reduced thrombocyte count. When actually the total count is, is normal. The most common situation we'll see this is when we're taking a blood sample and it's perhaps not a clean stick, and we get activation of the clotting cascade, and we can get clot formation in our EDTA tube.
And if we do have a clot form, then it will reduce the platelet counts when that's analysed. So it's an important one to be aware of because. I think if we ever have a patient that presents to us and we detect a thrombocytopenia, but it doesn't sort of make sense in the clinical setting for that patient, or there's nothing else to suggest that the patient, you know, might have a thrombocytopenia, then one of the things you should always do is recheck the platelet count, make sure that it is definitely accurate and that it's not after factually low.
So we then have iatrogenic, this is really, really uncommon cause of thrombocytopenia. It could be otherwise referred to as dilutional. So these would be patients basically who receive large volumes, of fluid or, or, blood products.
And essentially, we dilute out their thrombocytes in the bloodstream. So this is really quite uncommon and the degree of thrombocytopenia that's seen in these patients is really mild and not clinically significant. We then have decreased production because of bone marrow disease, so this can, certainly cause thrombocytopenia, but it really tends to do, .
Do so in combination with other cytopenias as well, so we might get a reduced white cell count, which of course called leukopenia, or we might have a concurrent anaemia. So the reason why we don't tend to see thrombocytopenia on its own with decreased bone marrow production is it's quite uncommon. For just one cell line to be affected in the marrow by a disease, and whilst we can see that with forms of sort of neutropenias and anemias, they're really quite rare and sort of more commonly, if we think about bone marrow disease, it tends to affect large proportions of the marrow.
And tends to affect multiple cell lines. So I think we'd be more interested in decreased production in a patient that presents with a bi-cytopenia, so two cell lines that are reduced, such as the platelet count and the neutrophil count, or a pancytopenia in which all cell counts are reduced, which would be much more suggestive of bone marrow disease. And then we've got the fourth category which is by far the most common reason, for seeing thrombocytopenia in our patients once we've ruled out artefact.
And within this group we have platelet consumption, destruction and sequestration. So an important cause of platelet consumption would be, bleeding. If we have a trauma, or you know, a spontaneous haemorrhage such as a heme abdomen, we're gonna lose our platelets, we're gonna consume them, during that bleeding process.
And we also have diseases as well like DIC, where we get widespread. Activation of clotting in patients, that can actually be so widespread and and so severe that it does start to reduce circulating platelet counts. And in DIC patients can eventually lead to quite a hypocoagulant state when patients start to then bleed out.
Destruction is what we're talking about, today, which would be, immune-mediated thrombocytopenia. And as we'll talk later on, there are primary and secondary forms of that, and it's sort of important to be aware of them and be able to differentiate them. We then have splenic sequestration of platelets as well.
So various diseases of the spleen, that are associated with splenomegaly can cause a buildup of platelets in those organs too. So we said with destruction of the platelets, there's basically two forms. So primary immune-mediated thrombocytopenia, is where there is no underlying putative trigger that's identified, and it does seem to be a primary autoimmune disease targeting the circulating, platelets.
But we do have secondary thrombo immune-mediated thrombocytopenia as well. In which the platelets are destroyed, because of an underlying disease process such as neoplasia, perhaps a parasitic disease, or, the patient has been receiving drugs which has triggered a mediated response against the platelets. So we'll talk about those in a bit more detail, when we think about how we're gonna diagnose primary ITP, you know, by ruling out the underlying causes.
Do bear in mind as well that, when we've got a low platelet count, of course that can affect clotting function, but you can also have a normal platelet count but have abnormal function because of thrombopathia. So thrombopaia is when you have normal platelet counts, those platelets aren't functioning normally and for whatever reason. And that can cause patients to have bleeding tendencies as well.
Some patients are unlucky enough to have both thrombocytopenia, and, thromboopathia, and, and could be at significant risk of of spontaneous haemorrhage. OK, so when do we get worried about bleeding then, in thrombocytopenic patients? Well, we know that there is excessive bleeding possible when we start to get reduced platelet counts, but generally they have to be below 50 times 10 to 9 per litre for that to become, you know, a significant problem.
So once we get below that value of 50, you are at risk of excessive bleeding, but you don't tend to spontaneously bleed until your platelet counts are much lower than that, generally below 20 times 109 per litre. So I think that's important to be aware of really, if we have a patient that presents with, you know, external, blood loss, and we're thinking, OK, they could have a coagulopathy if their platelet count is 70 times 109 per litre, they're likely, they've likely. Got a low platelet count, not as the cause of their coagulopathy, but as a result of the blood loss with their coagulopathy.
And in those patients, we wouldn't say, oh, you know, the platelet count is 70, which is low. They've got evidence of the coagulopathy, it must be an ITP. You would actually look for other causes in that patient other than ITP.
So it's important to be aware of some of these numbers, and when we're looking at treatment goals, certainly, in hospital treatment tends to occur in patients that have platelet counts that are, you know, lower than 20 to 30 times 109 per litre. So we really want to be sending our patients home with platelet counts above those thresholds so they're at as lower risk as possible of ongoing bleeding and deterioration. So when we see bleeding because of thrombocytopenia, we get quite a characteristic, set of clinical signs.
So we see petichiation, which are these pinpoint haemorrhages that tend to occur most commonly in the oral mucosa, as well as ecchymotic haemorrhages, which are these larger sort of coalescing bruises and that tend to occur most commonly on the ventrum of dogs with ITP. But we can also see patients presenting with bleeding from the nose, so epistaxis, and also bleeding into the GI, and urinary tracts as well. And certainly a really significant, volume of blood can be lost into the GI tract because it's bleeding, you know, from small vessels.
And we may also see patients presenting with ocular manifestations of this disease because of retinal haemorrhage and associated, you know, blindness. And or high femur, which is bleeding into the anterior chamber of the eye. And so this is a common sort of constellation of clinical signs that we see in patients with primary coagulopathies, so either those with low platelet levels, abnormal platelet function, or abnormalities of the way the platelets.
Interact with the vascular endothelium. So this is different from your secondary coagulopathies, which are to do with abnormal levels or function of the clotting factors in which we tend to see a different, Different types of haemorrhage in those patients. So we more commonly with those patients see sort of large hematomas forming injection sites.
We see bleeding into body cavities such as the pleural or peritoneal space, and we can see things like bleeding into the joints, which we call hemaarthrosis. So they are quite different in their presentation, primary and secondary coagularies. Here's just a picture on the left of a patient with small petechial haemorrhages in the mouth, and a patient on the right with sort of larger coalescing ecchymotic haemorrhages on their ventrum.
So up until this point, we've been talking about thrombocytes and thrombocytopenia in general, but for the rest of the talk we're really going to talk about dogs. And the reason for that is that thrombocytopenia, whilst we do see it in cats, it's quite an uncommon cause of coagulopathies in these patients, and certainly primary immune mediated thrombocytopenia is very uncommon. There's a nice review, sorry, a retrospective study.
From the JSAP in 2018, looking at the prevalence and diseases that were associated with thrombocytopenia in cats, and essentially the most common cause of low platelet counts in this study was artefact. So simply, you know, rerunning your platelet count, using a different method, which we'll talk about in a few slides, and realising that patient actually has a normal platelet count is, is very common in cats. When we did see.
Genuine thrombocytopenia in patients. And it was persistent, then the most common causes were infection and neoplasia in cats, and actually ITP was very, very rare in this study. So we're not going to talk about cats really for the rest of the talk.
Some of the things we're going to talk about like manual platelet counts apply to cats as well. But just do be aware that if you ever have a thrombocytopenic cat, you double check that platelet count, see if it's definitely accurate, you know, and if you have got a patient with the low thrombocyte count and you think it's definitely clinically relevant. Really, really, aggressively screen cats for secondary causes that ITP because primaries is much less, common when compared to dogs.
So talking about immune-mediated thrombocytopenia in dogs, we've said the disease can either be primary or secondary to some of the disease. Primary ITP is quite a common disorder and occurs due to platelet destruction within the bloodstream. So B cells migrate from the marrow into the bloodstream and are activated by circulating T cells.
These then mature into plasma cells, and produce antiplatelet antibodies, which binds to the circulating platelets and allow macrophages in the spleen and liver, to remove them from the bloodstream and and destroy them. So that drops your . Platelet count.
Now normally then, the marrow kicks out loads of new platelets, and for a period of time, the platelet count may remain static, but eventually the rate of destruction, outstrips the rate of production by the marrow and we start to see decreasing, circulating platelet counts. And it's important to be aware that you can also see destruction of the sort of platelet precursors that Megacurry sites at the level of the bone marrow, but it's really not common. So generally I mean mediated thrombocytopenia is a disease of destruction of circulating platelet counts and not so much those in the marrow, and that's part of the reason why a bone marrow sampling is often unnecessary in the investigation of these patients, unless you had a patient, .
That you're suspicious of a primary, you know, marrow disease. So we're now going to talk about primary immune-mediated thrombocytopenia, how we identify it, how we differentiate it from the other causes, and then how we treat it. So generally it's something that's seen in middle-aged, particularly female dogs.
And that's because middle aged female dogs are certainly overrepresented for all immune-mediated diseases, of which this is, . And there are some breeds that we do see significantly overrepresented, including cocker spaniels, old English sheepdogs and poodles. Most patients who present with primary immune mediated thrombocytopenia interestingly present to the clinic simply because of quite vague signs, often lethargy and weakness because of their blood loss anaemia, rather than the owners actually noting external blood loss themselves.
So I think it's quite important to be aware of that. So when we're doing our physical exam, we're having a really good look at the mucous membranes, a TA and eccymoses. You know, and do the rectal exam, to check for any fresh blood or evidence of melena as well.
When you've got a patient who presents with secondarymediated thrombocytopenia, they can certainly present with weakness and lethargy, but often they have other symptoms as well, due to their underlying trigger of that disease, you know, so significant weight loss and hypoorexia if they've got an underlying cancer, for instance. We mentioned what the primary signs, sorry, the signs of primary coagulopathies. Were earlier on, the tia, the ecchymoses, you know, hematuria, hematochezia, we want to check the mucous membranes as well for any pallor, because these patients will quite quickly develop, blood loss anaemia, due to their.
external blood loss. On abdominal palpation we quite often feel an enlarged spleen. Of course, the spleen is sort of being stimulated, to remove the platelets from the bloodstream.
We can often see an elevated rectal temperature as well, because of the inflammatory nature of the disease, but obviously don't let a normal temperature rule out, primary ITP. And we want to do a rectal examination as well for the presence of, Melina. So onto the diagnosis of primary ITP, it's essentially a diagnosis of exclusion where we document very low circulating platelet counts that be low enough to be consistent with immune-mediated disease, and then we rule out all the possible underlying causes, of secondary, thrombocytopenia in that patient.
We then put them on immunosuppressive therapy, and monitor the response. And essentially, if you've ruled out all the other causes of that. Severe thrombocytopenia and they respond to immune immunosuppressive therapy, then that's how you get your diagnosis.
In the, UK we don't have access to, antiplatelet antibodies as, as we do as a test in other parts of the world. So in the US for instance, there's a blood test, test, for antibodies against the circulating platelets, . Now that can be of some use in helping reinforce the diagnosis in the parts of the world where it's available, but also bear in mind that it's not 100% sensitive or specific for primary ITP so it shouldn't be relied upon.
We also want to be, as I say, screening for the secondary causes of ITP, so we're going to think about a complete history, particularly focusing on has the patient started any new medications in the last few weeks that could have triggered ITP, have they travelled outside. Of the United Kingdom, or to any other areas of the world where there's sort of endemic diseases that can cause secondary immune-mediated thrombocytopenia. So really knowing a lot about the travel history is important with these patients.
We're then going to perform imaging. To again screen for neoplasia in particular, as a potential trigger for ITP but also look for evidence of any infectious diseases as well. And then we're going to focus on infectious disease testing as appropriate based on the patient's travel history and and how they're presenting.
OK, moving on to sample collection, and we want to remember with these patients that we suspect have got a low platelet count that we only want to be getting our blood samples via peripheral sticks, so blood samples from the cephalic or subvenous veins rather than jugular vein and because of their risk of ongoing uncontrolled haemorrhage. And we want to put lots of pressure on for a good 5 minutes after we take the blood samples, and just double check that there's no evidence of ongoing bleeding before we send that patient away or put them back into their kennel. We want to get samples in all patients with coagulopathies for a variety of testing, and it is genuinely best to get these samples as early as possible before anything else that we do.
Potentially interferes with test results, such as administering immunosuppressive medications or transfusing with blood products. So we want to get a CBC performed as early as possible, so a haematology complete blood count with a fresh smear. So we'll need an EDTA blood sample.
And once you've got the sample and mixed the EDTA tube, we immediately want to make a fresh smear. So this is one of the absolute take homes of this talk is the utility of fresh blood smears. And how every single time you run a CBC, you should be making one of these to either send out with your external CBC to the external lab if a pathologist is going to look at it because that's a prerequisite, or if you're going to run a CBC in-house having your own fresh blood smear, so you can look at it and double check that the numbers that you're seeing on the analyzer are accurate, and we'll talk about that in a few more slides.
We want to be running biochemistry profiles in these patients as well. So we're screening for any evidence of systemic diseases, we're looking for complications of blood loss, so hyperproteonemia, etc. Etc.
And you should always combine a biochemistry with a urinalysis as good practise, and we want to be getting this urine sample free catch rather than via cystocentesis because these are coagulopathy patients and you can increase the risk of significant bleeding by performing cystocentesis. We will want to do a coagulation profile in a lot of patients as well. So that would be various blood tests including PT, APTT, fibrin degradation products, and D dimers as well.
And these are tests that can be run, some of which in-house, if you've got some of These analyzers in your practises, but otherwise they're generally run in external reference labs, on citrate tubes. So make sure you've got a citrate tube in these patients if, if you can get it, and make sure, you know, particularly your EDTA and citrate tubes, you're filling it to the appropriate line, because under or overfilling some of these tubes can affect the test results. So this sort of coagulation profile is more to screen for secondary coagulation problems, so disorders, of the clotting factors themselves.
And in ITP patients, it is just a reduction in, in the platelet count, and, you know, the PT, APTT, FTPs, and D dimers should all be, within normal limits in these patients. So it's just to help you rule out, other coagulopathies. And we're then gonna do some infectious disease testing as well.
Based on the travel history, so that might be a Babezia PCR or an EDTA sample. It might be, the IDEX 4DX snap test for our Lia, or. And a plasma, in a patient with a travel history to endemic areas, that's done in a serum gel tube.
So just make sure you've got the right tubes for the right sort of relevant tests. And bear in mind as well that certainly in the UK. Where we have, endemic androstroloszorum or lung worm, that parasite itself can cause coagulopathies, and as part of their coagulopathies, you can see pretty significant thrombocytopenia in those patients.
So certainly if there's not an up to date worming history, or the patients were in an endemic area, testing for angiostrolus would be reasonable as well. We might also want to blood type our patients. If we're worried about having a blood loss anaemia, then there's a possibility of needing to transfuse them at some point.
I said earlier that bone marrow sampling is pretty uncommon in these patients, and we only really consider it when we've got concurrent leukopenia, to be honest. To point us towards a more generalised, bone marrow problem. But do bear in mind that thrombocytopenia itself is not a contraindication to bone marrow sampling.
So you can sample patients with very, very low platelet counts, you know, and whilst they can bleed more than a patient with a normal platelet count, it's really uncommon for there to be any, significant complications of, of bone marrow sampling in a thrombocytopenic patient, which is obviously quite different from, various other sort of surgical procedures. So just talking about blood smear evaluation, I've said it's really important to look at a blood smear in every patient that has, abnormalities of clotting, in particular, any abnormalities on their hemogram. .
But one of the things that we're going to just talk through in the next couple of slides is how to do a manual platelet count. So essentially the machine spits out a number and it says, you know, 100 times 109 per litre, and we say, OK, that's sort of a mild to moderately reduced platelet count. Let's check that for myself on the smear just to be sure that it's not artefact.
So you make a fresh blood smear, and you diff cricket, and then what we're gonna do is put that, smear under the microscope and we're gonna go up through the different lenses until we are on the high magnification lens, which is the 100 lens. And what we're gonna do is look at the monolayer of the blood smear, I'll show you where that is in a second. And we're gonna look at the monolayer and start to count the number of platelets we can see in each high-powered field.
OK? And what we do is we count the number of platelets in each field, and we sort of do 10 fields and then calculate the average number of platelets per high powered field, and then we times that number by 20, and that will give us, the patient's platelet counts as if it was a machine analyzer, and that allows us to double check the results we're getting from these in-house analyzers to be sure of whether they're accurate or not. This technique also allows us to assess the red cells to see if there's any evidence, of concurrent, immune mediated anaemia.
So is there any evidence, of ghost cells or sporocytes which might point us towards a diagnosis of Evans, which is concurrent IMHA and ITP. And so just to show you quickly, exactly how we do this manual platelet cam. So this is a stained blood smear, and at the top of this sort of smear here we have the feathered edge.
So this is an area that we're initially going to look at for any evidence of platelet clumps. So as I said, if you get early activation of the clotting cascade and as you're taking a blood sample and you get sort of blood clots or clumps starting to form, you'll have an artificially low platelet count. So one of the things that you do is have a look at the smear and say, OK, are there any sort of platelet clumps forming?
And if there are, your machine count will be art of factually reduced and you know you need to repeat your sampling. And, but for the purposes of doing a manual platelet count, we're going to concentrate on the monolayer. So this is this area here just behind the feathered edge where essentially the smear is quite dense with cells, but the cells are not sat on top of each other, so there's sort of one cell thick in this layer, hence the name monolayer.
So what we do is we Have a look at this area here, and we go up through the lenses to our time zone lens, which should look something like this. So this is one high powered field on the times 100 lens and what we will do is have a look and see if we can identify platelets. So platelets are these small sort of more purple staining cells that don't have a nucleus.
That are smaller than red blood cells. You can see one here, one here, one here, one here, and what you do is count the number of these platelets on each of these high powered fields. So I've gone ahead and done that for you.
So I've circled each of the platelets that I can see, and if we count them up, we've got 123456789, 1011, 12, so I can see 12 platelets on this high powered field. So what I do is times that number by 20, and that will give me the patient's platelet count. So for doing this manual platelet count, I've estimated that the patient has 240 times 109 per litre circulating platelets, which is a normal platelet count, OK?
So generally when you're seeing 8 or more platelets per high powered field, that's sort of consistent with at least a normal count or above. OK. So if you're not doing this routinely, I highly recommend you get into the habit of making blood smears of doing this and just getting familiar with the technique, because certainly working at referral level.
I've seen quite a few cases that come over and part of their clinical picture is a thrombocytopenia and one of the first things you do is check a blood smear and lo and behold, in quite a few of those patients, their manual platelet count is normal, and I can sort of disregard their low platelet count on the analyzer as artefacts and concentrate on the other problems that patient has got with my investigations. And this is just a nice photo of actually a circulating mega carrier site, which is these two sort of large blue cells in the centre of the image with these much smaller platelets fragmenting off of them. So as I say, these are abundant in the bone marrow, but you can also see mega carrying sites peripherally as well.
So what do we do when we see thrombocytopenia and anaemia together? Well, there's a few reasons why I could see both of those, and this is the way I tend to think about it. Essentially, if we have, bone marrow disease.
What we'll typically see is a thrombocytopenia with a non-regenerative anaemia. OK? And we may or may not see leukopenia as well.
So one of the things we need to do when we've got thrombocytopenia anaemia is determine whether that anaemia is regenerative or not. And if you're happy to look at a smear and do that in-house, that's great, but otherwise, sending the blood out, to a pathology lab, for a smear analysis and a reticular cyte count is sort of highly recommended. .
If we see thrombocytopenia and secondary blood loss anaemia, so for instance, the ITP patient that's bleeding into the GI tract, and these patients will have low platelet counts, and they will initially have a pre-regenerative anaemia that over a few days, 3 to 5 days, will become a strongly regenerative anaemia without any evidence of homolysis. OK, if, however, the third sort of situation occurs and we have immune mediated thrombocytopenia and immune mediated hemolytic anaemia, which we refer to as Evans syndrome, then in these patients we'll have both low platelet count and low red blood cell count, but essentially, The red cells will generally be consistent with a very regenerative anaemia because hemolytic anemias are generally very regenerative, and there'll be evidence of homolysis as well, such as spherocytes and ghost cells on the smear, but also positivity of in saline agglutination and Coombs testing. So be aware that we can see both ITP and IMHA in some patients.
So that's about 20% of our ITP patients they have both. We refer to this as Evans syndrome. And Evans syndrome certainly confers poorer prognosis than just having ITP in isolation.
So the goals of treatment are to slow platelet destruction, stop bleeding, and treat the concurrent disease if we've identified one. We're going to have these patients hospitalised generally for the first few days of treatment if they've got particularly low platelet counts, and whilst they're hospitalised, it's pretty sensible to have some. Standardised precautions that everybody in the practise is aware of when these patients are in the hospital.
So things like having them in a well padded cage, with minimal handling to help reduce, bruising or, or any worsening of any bleeding, feeding a soft diet might be beneficial to help with sort of small amounts of trauma to the gingiva with dry food that precipitate some bleeding from the mouth. Good signage as well to make sure that everybody's aware that that patient is thrombocytopenic and therefore, it's contraindicated to take jugular venal puncture samples in those patients and to stick to peripheral blood sampling where possible and to avoid any subcutaneous or intramuscular injections because of the risk of excessive bleeding. Patients that present hypovolemic because of significant GI blood loss might require fluid resuscitation of their hypovolemia.
And of course if the patient is on any drug that would, decrease platelet function, so any sort of antiplatelet drug, that should be discontinued as well in this patient. The treatment with blood transfusions plays a role in the ITP management, primarily to boost red blood cell mass in anaemic patients that are transfusion dependent because of significant GI blood loss. And we don't tend to use transfusions to boost platelet counts.
And that is because, firstly, there are no platelets in in packed red cells, and in whole blood, the platelets don't really survive the transfusion very well, and aren't particularly functional. There is, a new product that's just become available through the pet blood bank in the UK, which is a, a platelet, concentrate transfusion. So this could be considered in patients with severe ITP.
However, it's only able to really offer very short term improvements. In sort of clotting for patients that are suffering the most severe life threatening haemorrhage. And in patients with immune mediated thrombocytopenia, these transfused platelets don't tend to boost the overall platelet count very much because they're destroyed very, very quickly.
So unfortunately, whilst it might seem like an excellent solution for these patients, even transfused platelets in concentrate and are not likely to be a particularly robust answer in these patients, and instead, just the transfusion of red cells, in the anaemic patients really is the mainstay of transfusion therapy in these patients. So otherwise, the cornerstone of treatment is prednisolone for primary ITP and we're looking at starting immunosuppressive doses, so at least 2 to 4 migs per gig per day initially. We can use dexamethasone as an alternative if the patient, is too unwell to be orally medicated or is too aggressive.
the dose is in the order of 0.2 to 0.3 mg per cake, per day.
And what we tend to see with prednisolone therapy is that it has its effect within the first week and platelet counts initially continue to decrease during the first few days of treatment before they then tend to plateau out and then start to go up at around the sort of 3 to 7 day mark. And once patients' platelet count has started to go up, that's when we get a lot less worried about those patients. And once we get above the 20 to 30 times 109 per litre mark, that's the point at which we can often consider discharging patients from the hospital.
And once outpatients, we tend to monitor platelet counts and of course red cell counts if they've been reduced, at least once weekly. And once the platelet count has normalised or or is near normal, we can start to down titrate the dose of prednisolone. So typically 25% every 3 to 4 weeks.
Whilst monitoring the platelet counts, the prednisolone is continued for often 4 to 6 months, slowly doing treating the dose every 4 weeks. And once we're on a really low dose, so something in the order of 0.5 to 1 mg per gig every other day with a normal platelet count for about 4 weeks, we can then generally discontinue the medication.
Now there are potential benefits of using a second immunosuppressive agent in combination with the prednisolone. And I think particularly those benefits are to help reduce the doses of prednisolone that we have to use to control the disease, particularly in dogs that are at risk of significant steroid side effects. So for instance, very large breed dogs are much more likely to develop muscle atrophy and weakness than smaller breed of dogs.
Dogs also that, for instance, have had a history of GI ulceration or are at significant risk of developing diabetes, for instance. And we might want to get them on a lower dose of prednisolone a bit earlier. And using combination therapy with other immunosuppressives can allow us to do that.
However, there is no sort of, Overall benefit to outcome that's been identified in the literature when comparing steroids as soul therapy versus steroids and additional immune suppressives. So we've got a few options here for second line immunosuppressives. Typically we think of mycophenolate, Moffattil, azathioprine, and cyclosporin.
And there's no sort of strong evidence, to say that one is any better than the other. There is some evidence that mycophenolate mfatil potentially can be preferential, to cyclosporin, and certainly, there's evidence that in patients that cannot tolerate prednisolone at all, mycophenolate mofatil can be used as a sole therapy. To control ITP, in some patients.
So that's important for a patient that just cannot, be put on prednisolone for, for whatever reason. When we're deciding about these drugs, really we need to weigh up, the pros and cons of each drug. In light of the individual patient that we've got in front of us, so thinking really about the side effect profiles of these drugs, how long they take to have their effects, potential costs, and how we're going to monitor these patients as well.
So, you know, certainly any of these drugs would, would be, justifiable choices in the individual. I think talking about them in great detail goes kind of beyond the scope of, of this lecture. I did want to talk, however, about the use of vincristine, so I think this plays a really important role in the treatment of the hospitalised ITP patient.
So Vincristine, which is traditionally used as a chemotherapy drug, has also got a role in increasing platelet release from the bone marrow. So this is interesting whereby we get sort of release of more juvenile platelets earlier on, from the marrow, to help increase the circulating platelet count. Now, this can be really beneficial in our patients, that are in the hospital with very low platelet counts, and particularly if they are sort of failing to respond to prednisolone, after several days of hospitalisation.
And the drug also has its benefit by being able to inhibit macrophage phagocytosis of platelets, so it helps to reduce the destruction of the circulating platelets, and also reduces antiplatelet, antibody formation, adhesion to platelets as well. And the use of the drug was looked at in a recent study where they looked at use of prednisolone alone versus prednisolone and Vincristin for the treatment of hospitalised ITP patients. And essentially Vincristine was very well tolerated in these patients and decreased the length of hospital stay.
By an average of 2 days. So whilst vincristine isn't necessarily cheap to administer because it's, you know, a cytotoxic drug and there's all the PPE that we have to use and then the sort of nursing precautions thereafter, the use of a single dose of vincristine, if it does decrease the hospital stay on average by 2 days, that might drop the bill for the patients significantly enough, that it, it certainly pays for itself. And can speed up, you know, increases in platelet counts and time to discharge.
And there was also some concerns with regards to the use of incrystin, however, that when it does increase your circulating platelet count, those platelets might be juvenile and nonfunctional, but there was a sort of recent study in the JSAP in which they looked at the sort of functionality of these platelets. And found that they did appear to be normally functioning platelets. So, it's certainly, it is, it's something to consider, for the use in hospitalised ITP patients.
We've then got human intravenous immunoglobulin. So this is something that is quite hard to get hold of, currently in the UK. There's not a lot of it going around for, for the human medicine profession, and as a result it is quite hard to source.
It is also very, very expensive as well. But essentially, it has been shown in, in a couple of studies to really rapidly increase platelet counts, and you know, can be used as a sort of rescue therapy or even in some cases a first line therapy for patients with severe immune-mediated thrombocytopenia. It works by blocking the FC receptors.
On the mononuclear phagocytic cells, again, to stop them, from binding to and destroying the circulating platelets. So I think this is something that could be considered, in patients that are sort of refractory to standard therapy, but I don't think based on cost and difficulty sourcing it, it's going to be a first line treatment in many of our patients. We've then got the option of splenectomy.
So splenectomy might seem counterintuitive in a patient that's got very low platelet counts and obviously bleeding tendencies. But with, you know, a good surgeon, with good hemostasis, the risk of splenectomy, potentially. Doesn't outweigh, the potential benefits in a patient that sort of has failed to respond, to other therapies.
So there was a recent study from the JVIM published in 2022 where they looked at splenectomy for the management of primary immune-mediated hemolytic anaemia. And primary immune-mediated thrombocytopenia as a sort of rescue therapy and essentially what was found was that it wasn't particularly successful for the treatment of the IMHA patients, but actually it was pretty successful and well tolerated in the ITP patients with 6 of the 7 ITP cases in the study being successfully managed with splenectomy. So I think it's definitely something to consider in the treatment refractory ITP patients.
As an alternative to human intravenous immunoglobulin, but obviously, I think we have to be very, cautious about the risks of significant haemorrhage, and also things like wound dehissants, in patients that are probably, you know, already receiving immunosuppressive doses of glucocorticoids, and even other immunosuppressive agents, you know, at the time of surgery. Well, the treatment, considerations, well, we mentioned earlier fluid therapy, for the hypovolemic patient because of GI blood loss. Gastroprotectants is something that, that might be worth considering.
And when, when we're thinking about, patients with ITP, obviously we sort of worry about this GI blood loss, and a lot of patients are started on gastroprotectants as a result of that. I think we have to remember that the GI blood loss is bleeding through small vessels, not ulcers and erosions. So really, in theory, there's no reason why a gastroprotectant would be indicated in, in a true ITP patient.
I suppose the worry is that with some of our ITPs we become very anaemic and that can cause gut wall hypoxemia. We then combine that with high doses of prednisolone, which can be ulcerogenic, and that there is the risk then of ulceration and erosion, and we wouldn't really be able to determine if that patient has GI bleeding because of their ITP and and loss of these small vessels or an ulcer or erosion. So I think.
Gastroprotectants potentially can play a role. If we think there is really significant GI haemorrhage, we can't exclude ulceration or erosion, and we can start patients on the drug, but I think starting patients sort of routinely on, on gastroprotectants is probably unnecessary. Certainly, once they're well enough to become, you know, outpatients, because we also know, that there's very little evidence, to support prophylactic use of gastroprotectants in preventing GI, ulceration or erosion.
Other nursing considerations we've we've sort of mentioned earlier really, about how we care for the patient that's thrombocytopenic, . And then finally on to prognosis. So when we're looking at outcomes in patients, mortality rates can be concerningly high in the order of 25 to 30% in some studies, and normally patient mortality occurs because of severe GI haemorrhage or euthanasia because of lack of response to treatment or costs.
Negative prognostic indicators that have been identified previously include a high, BUN, so, you know, indicative of significant GI blood loss, digested blood, obviously increasing, the BUN, or melena being present as well. Long-term medications are needed in as many as 25% of patients, and relapse rates can vary, anything from 15 to 40%, whilst on treatment or, or when patients have come off of treatment. So these guys do need to be, sort of monitored.
Long term, whether that is with, sort of observation just by the owners at home, or potentially intermittent blood sampling in the clinic to check thrombocyte counts. OK, so you'll be glad to hear that's the end of the talk. Thank you all for listening, and I hope you've taken home a few sort of pointers to help you with the diagnosis and management of these patients in primary care practise, and good luck with these cases because they certainly can be quite challenging to manage, but nonetheless often quite rewarding as well when you do get a good outcome.
All right, take care.