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you're not going to get asked that much about, uh, so if you pay attention, pay attention at the start, pay attention at the end. Um, and then that's it. You can zone out to the middle bit if you really want to. So we'll start off with some questions. Um, trying. I'm going to try and keep as interactive as possible. You can either unmet yourself and say what the answer is. You can type in the chat. I really don't mind you getting it wrong. Um, or if you don't want to answer at all, so I'll give you a minute or so if that's okay. Sorry. My laptop stuffed up. Awesome. OK, so, uh, you mentioned, uh, folate B 12 deficiency. Anything in particular? Any? Do you want to commit to one or the other? I know that's hard, but yeah, really good. Megaloblast anemia. Very nice bullet. Okay, awesome. Fine. Okay. Very nice. Follow deficiency. Basically, we'll go over all these questions. Um, and we'll talk about each topic in particular. Okay, So the next one. So a five year old boy presents to a and e. He's got fatigue, shortness of breath. Uh, he's slightly jaundiced, and his peripheral blood film shows is shown below. His father had a splenectomy when he was younger. Now, this is the hard bit of the the question. So what is the most sensitive investigation? So I'm sure a lot of you will be able to tell me the diagnosis, But generally what happens in the path exam is you're going through the first three lines. You're like, I've definitely got this and they ask you something completely different. Um, so if you can give it a go. Nice. Good thinking. Okay. Awesome. Megan Really, really good. Okay. So, yes, you are right. And I will go over what? Either the mean ear made binding. Awesome. Yeah. Fantastic. You guys are smashing it already. Okay, fine. I'll talk about what Either Both of those are so both asthmatic fragility and this one as well. Okay, next question. So you've got an 18 year old. He's just come back from holiday to Malawi. Uh, he's booked a GP appointment, and he's basically turned yellow during his holiday, and he had brown urine and he felt way more tired than usual. Uh, he took antimalarial prophylaxis as directed, and his blood tests reveal enormous citic anemia with unconscious gated, uh, bilirubinemia. Um, that is negative. And what is the most likely reason for intravascular hemolysis iss, So I'll give you another couple of seconds. Awesome. Nice. Yay. Anything else anyone else suggest? Anything. All right. So I think everyone is in agreement with G six PD. Awesome. Really good. Okay, um, and this one is important. They don't tend to ask negative questions at Imperial, but it's a nice one to understand. If you know why everything else can be ruled out. It means that you know the topic pretty well. Um, so which lab finding would you not expect to have? An autoimmune hemolytic anemia? Okay, fantastic. Brilliant. OK, Raised, uncontrolled, raised, conjugated bilirubin. And I'll explain why that's the case. Okay. A lot of people get confused with these topics. Uh, so a confused patient presents to A and e. Uh, she's noticed to be extremely lethargic. She's oliguric. And her blood film shows schistocyte so schistocytes are basically broken up. Red blood cells. Uh, blood show a thrombocytopenia so low platelets and a rapid rise in urea and creatinine. So what is the most likely diagnosis? Okay, so We've got some suggestions for number three. Some suggestions from Ah ha. Okay. So bit stuck in between the two of them. Okay, fine. Good. That's exactly what we wanted from the question. So it's fine if you get it wrong. So the answer is T T B. And I'll go over. Why? In a second? Okay, so the next question is about TTP. Uh, so how do you manage it? So I think if if the exam is still the same as what we did, there will be a mixture of both, uh, like, single best answers. Um, and a little, uh, written questions as well. Plasmapheresis. Yeah, decent. Anyone else? Okay, fine. So yeah, basically, plasma exchange is the main thing. Um, Okay, so the first topic is anemia, and I know you guys probably know something about it. There are some things you probably get confused about. Um, but generally you guys are probably doing well. Let me move this. I'm sorry. I didn't realize I was in the way. Okay, So, um, basically, um, you've got reduced ability to deliver oxygen because of a low amount of red blood cells or a low amount of hemoglobin So in men, we say that's about 1 30. In women, we say that's about less than 1 20. And the mechanisms for anemia are very obvious. So you got blood loss. You've got decreased production and increased production. So blood loss could be from trauma. It could be from GI Bleeding. Decreased production would be something like iron deficiency anemia, B 12 deficiency, thalassemia, malignancy and then increased destruction would be something like hemolytic anemia and anemia and generally in pathology. The best way to think about things is to try and figure out how it's classified, and you can kind of work things out for it. So anemia can be classified by size. So microcytic, normocytic and microcytic, and then you can we'll see in a in a second. Another way of classifying any is as well. So the key differentials for a microcytic anemia. So, um, microcytic basically means you've got a small MTV, so the size of the cells are really small, so the key differentials are iron deficiency, anemia, thalassemia, sideroblastic anemia. So the first thing when they show you a blood film and they expect you to to try and figure out what the cause is is you want to have a look at the MCV and see what the size of the cell is, and then you'll go straight to these three differentials and then you'll try and figure out in the question stem. If there's anything that can set you aside with these investigations, you definitely want to do is a peripheral blood smear, and that's to see what the cells look like on on the outside. So, uh, whether the cells look small whether they look if they've got additional cells in them if they've got bite cells, Hines bodies or that kind of stuff really important that you detect in the in the peripheral blood smear, Um and you'll definitely want to do iron studies. And by that, what we mean is things like ferritin transferring TIBC um, and that will help you differentiate so iron deficiency anemia on the blood film. This is just a key, like a key phrase, like a little buzz word pencil cells. So if you see pencil cells, think iron deficiency anemia. Um, now, when you look at the iron studies, your iron is obviously going to be low because we're talking about iron deficiency anemia. Your ferritin is basically a protein, which, which stores iron and releases it in a controlled fashion. Now, if your bloodstream has low iron, you're basically try and stop storing as much iron in the body as possible and try to release as much as possible. And as a result, your ferritin goes down because you released all your storage of iron you're transferring is basically what it's a. It's a molecule which flows around inside of your your bloodstream and binds onto iron as much as possible and your transfer and basically goes up because your body wants to to have iron as much as possible. So it brings all these molecules on which will help bind to the iron. Uh, TIBC is directly proportional to transferring. So if your TIBC is high, you're transferring tends to be quite high as well. Um, and then you might want to have a look in your your full blood count for, like a reactive thrombocytosis as well. Um, so the management is basically investigate the underlying course and then iron supplementation, so they're bleeding a lot. Figure that one out. So, for example, if you've got a, uh, a person who's had colorectal cancer for maybe a year or so undetected, they're likely to have a microcytic anemia or maybe a normocytic anemia. You want to investigate that with things like colonoscopy, um, and then treat it accordingly. Okay, so, thalassemia, we'll talk about this a bit more later. Uh, but the way that you're going to differentiate this so it's again to microcytic anemia so low MCV and a low HB And you're thinking between iron deficiency, sideroblastic and thalassemia. And the way that you're gonna differentiate is by the blood film, and you'll see something called Basophilic stippling. And that's basically an aggregation of ribosome A while, uh, material. And you get these little purple spots. So if you can look at the diagram, you see, like loads of little purple spots all over the place. Um and that's all ribosome, uh, material. And they're like remnants of like ribs oval, R N A. Your target cells are the cells that we can see here which look like a target, and they've got a central area of staining and then, like a nice, uh, like ring around it, which is a bit lighter in color, um, and the main causes of target cells. So target cells aren't specific for thalassemia, but you can find them often in thalassemia. Uh, so other causes of, uh, target cells would be things that stop, uh, stop you like regulating your blood blood, uh, as well as possible. So things like having a hyper hypersplenism or hepatic failure. Or like thalassaemia and hemoglobinopathy. He's, um and the management is with iron supplementations regular transfusion and then I insulation. So I regulation is things like, uh, there's four oxy mean where you give a substance and it binds to all the iron, which is like floating around in the bloodstream, and it gets rid of it. So this is the way that we're going to. This is like a nice summary table, which you might want to use in your in your revision. Uh, slides have been sent out to you, so it's It's just one that you might want to have a look at, maybe the day before the examination, just so you can get your head around what's high, what's low and why it is. So, for example, we were talking about iron deficiency and then, uh, anemia of chronic disease, which we will walk onto in a second. But the difference between these two, the way that you can tell the difference, is your ferritin so ferret. And we talked about which was your your basically your body's way of showing how much iron is stored. So in iron deficiency is low in anemia of chronic disease. You actually don't have a problem with the amount of iron in your blood. But your body doesn't want your like the the disease to use up this iron, and as a result, it increases the amount of ferritin that you produce. So you store it away, away from the disease or away from the infection itself. And in thalassemia trait, almost everything is normal. Uh, I just have a look. If there's any questions, Um, yeah, basic. So basically, so ribosome. Will stuff come from basophils? The reason why um, it's, um, it's called basophilic stippling is because the same stain that you can detect basophils with tends to just show up with ribosome. All r N A. So there's just a big overlap. So it's kind of like a little, um, it's almost like a little side product of that examination. So you're testing for Basophils and they come up as a nice purple color and then also all this river zonal d n A tends to come up as a purple color. Now, I'm not sure if that's because basophils have a lot of ribosomes or d n A. I don't know that at all. I thought it's just like a little side product of that same investigation. Um, okay, so sideroblastic anemia. So you've got loads of iron in your in your body, so you've got you've got all the iron that you want, but you just can't incorporate it into the hemoglobin. Um, sorry. So you just can't incorporate it into the hemoglobin and you basically end up getting loads of iron around your hemoglobin. And so it's basically they're called iron laden mitochondria. So you've got loads of iron just getting stuck in yourselves. Um, and you can get acquired causes, and then you can get congenital causes. Uh, so consider a plastic anemia. The way we're going to differentiate from the other ones is that your iron is high and your ferritin is also high in iron deficiency anemia. You're probably not going to have a high I and you probably have a normal iron. Your ferritin might be high. It might be a bit low. Uh, sorry. Your ferritin is going to be high or normal. Um, but compared to iron deficiency anemia, the ferritin is the one that, like, really, like, differentiates the two. And if you have something called ring Sideroblast, which is what we can see in this image, it's all that iron just stuck there. Um, then it's basically pathognomonic of sideroblastic anemia. Especially when there's no other cause of it. Um, acquired causes could be excessive alcohol use as well. Um, And then lead poisoning is another acquired cause of sideroblastic anemia. So if the only thing you can see in the history is, uh, to do, uh, it has nothing to do with alcohol or lead poisoning or anything like that, then it could be a congenital sideroblastic anemia, especially if they say that their parents had something similar to that as well. Okay, so moving on to microcytic anemias. So the main differentials is megaloblast ick anemia. So that's the ones that we were talking about the for in the first question. So that's vitamin B 12 and then folate deficiency. Uh, then you've got alcohol and then hypothyroidism. So basically, how does alcohol cause a macrocytic anemia? So, uh, Microcytic anemia in liver disease is basically when you have an increased amount of deposition of cholesterol on the red blood cell membrane, and when you get too much deposition of cholesterol, it increases the size of it, and as a result, you'll get a larger cell size, Um, and then hyperthyroidism. Basically, what it does is it, uh, T s well, TSH in particular, Uh, which goes up in hyperthyroidism because you're trying to cause your thyroid thyroid to increase the amount of thyroxin in your bloodstream. TSH also helps the production of erythropoietin. So now if you get a reduction, uh, sorry. Your you can scrap that your thyroxin hormone increases the amount of erythropoietin that you have. So in hypothyroidism, you're not getting enough t four and t three. And as a result, you don't get enough erythropoietin, sis, and as a result, you get, uh, an anemia in in in the process of all of that, does that make sense? I think I've might confuse someone in that last one. If you want clarification. Let me know, and I'll go over it again. Um ok. Doesn't look like anyone's got any questions so far. All right, So, uh, the key investigations are your peripheral blood smears your LFTs because you want to rule out alcoholic name disease and TFTs Hang on to say, um okay, no questions. Uh, all right. Okay. So megaloblast ick and m e a r b 12 and folate deficiency. Uh, your B 12 you get from your things like meat, fish, eggs, dairy products and then your folate deficiency. You get from, like, your leafy green vegetables, cabbage, kale, all that kind of stuff. Um, now, B 12, If we don't know, there's basically a process that you might have learned about in first year, which you've completely forgotten. But you want in the citric acid cycle. Uh, specifically, there's a co enzyme which you need to produce, called succinylcholine. A. Uh, you get this thing called methylmalonic Mallon OIC acid, which forms succinylcholine. A. Uh, Now, if you don't have vitamin B 12 as a cofactor, your methalonic manure. Ick acid. Sorry goes up because you can't convert into succinylcholine. So you get loads of this precursor molecule, But you don't get enough of the succinylcholine A, um and yeah, so basically, that's the way to do it. And then shillings test is basically a way of looking at pernicious anemia, which we don't really use anymore. Um, and it's looking at the way or how well, our body is able to absorb B 12 from the digestive system, so it's a bit of an outdated one. I don't think they'll ask you anything about it in the examination. And then the management is literally with supplementation, so we can either give folic acid. So if you've got a this might be useful for your, uh um as well. So if you've got a pregnant lady, then they've got risk factors. You might wanna give them 5 mg. If not, then you give them 400 micrograms for folic acid and then B 12, you just give a regular supplementation, usually by injection. Okay, so you got your non megaloblast ick anemia. So these are still your large MCV um uh anemias. And the way you differentiate them is just purely through the history and then clinical findings and bloods. So history. Obviously, if you're an alcoholic, you got a pretty solid history there. If you're hypothyroid, then you're gonna have a thinning of your eyebrows. You're gonna be bigger than usual. You're gonna have a low metabolic state. Uh, you might have a bradycardia intolerance to cold, all of that kind of stuff. Um, and then pregnancy pretty box down, and you'll know what that looks like. Um, clinical findings that you might see in alcoholic liver disease is a hepatomegaly. Uh, if they've got really late stage cirrhosis, your liver tends to get really small, so you might not be able to feel anything there. And then you get all your signs of chronic liver disease, so that might be, uh, in your hands. You get your Palmer erythema, you've got your jointness. If they've got decompensated liver disease, you've got cities, gynecomastia, spider, Niva, all the all the stuff there, and then your liver function test specifically for alcohol. So alcoholic liver disease, you're going to have a high A S t two a. L T. Ratio. So you're a S t usually is in 2 to 1. Um, and then you'll get all your A S. T s and A L T. So everything that measures hepatic function would also be raised. Um, so I'm not sure if you guys still have the same campus lecture with Mirren, but I remember that he had a really nice lecture where he was talking about the zones and the liver. Um, so you'll get different enzyme released depending on the zones, which are effective. Um, and then your thyroid function tests. I'm sure you guys know So you've got high thyroid stimulating hormone, which is produced from your hypothalamus, and you've got low t three t four because your thyroid is not working very well. And then the most common, uh, antibody, which is, uh, reduced is your, uh what? Well, you got increased anti thyroid peroxidase antibodies, and again just treat the underlying cause. Okay, so normocytic anemia. Um, the way that I would differentiate it is again by thinking about the classification. You've got hemolytic and nonhemolytic, and then in your hemolytic, you've got inherited and acquired, um, and your key investigations or your peripheral blood smear your direct antiglobulin test your CRP and your esr. Uh, just have a look for any questions. If the patient has both full and B 12 deficiency. Which one do you replace first? Yeah, you're usually replace. So your B 12 you're gonna that's gonna have happened over months. And the symptoms, like the symptomatic side effect of having B 12 deficiency, would be sub acute degeneration of your spinal cord, which is a medical emergency. Uh, so you probably want to replace your B 12 1st. Your folate is more important for if they're pregnant or if you're thinking about having a kid. Uh, then that's when you could probably replace that one. Uh, there's not. There's very little scenarios where you're you're stuck, and you're like You're in a and E and they have a low B 12 and low folate. It's very hard to get B 12 deficiency. Um, it's it's less and less common. You're seeing more and more cases with, uh, nitrous or like laughing gas use so that can cause subacute degeneration and spinal cord. And it's something to do with your B 12 regulation. I'm not too sure what it is. Uh, but yeah, so yeah, really good. Um, so, Tolin, you've You said that exactly. Right. So, b 12 1st and then you follow it afterwards. Okay, so anemia of chronic disease. This one is kind of like no one really knows what it means. Um, it kind of makes no sense. So basically, it's it's kind of a theory as to what goes on, but what really happens. It's multifactorial and your immune system. Basically, it's active, activated by auto antigens. Um, and then this increases loads of cytokine, cytokine production and free radicals. Um, and then this increases your this molecule called hep side in, um and then hep side in increases the amount of erythropoietin you produce, and as a result, you reduce the short the half life of a red blood cell. So anemia, chronic disease, loads of size, cons, loads of free radicals. You get an increase in this molecule which stops your red blood cell production. So hep side and stops. So hep side in is C I D i n. So the way that I used to remember is that I n stands for inhibitory molecule. Basically, that's the hep side in there. Um, obviously, that doesn't work when you got ferritin and transferring as well. Sorry, that's probably a bad one to remember. Um and then this decreases your e p o. Um, So the way that you're gonna remember anemia chronic disease is obviously they've probably got an underlying condition which is causing this, uh, that could be things like SLE or malignancy. Uh, any sort of long term condition which hasn't been treated well, cause an anemia of chronic disease. Uh, and in your iron studies were going to differentiate it by having a look at the iron. So, like we said before, there is no reduction in the amount of iron that you have in an in anemia of chronic disease. Your ferritin goes up because basically what your body wants to do is store it away from your bloodstream. So this disease that you're suffering from can't use that iron. Uh, that would be the opposite of, um, uh I iron deficiency anaemia, where your ferritin will be low because you're trying to release as much iron from your stores into your bloodstream. Uh, you're transferring is low because you don't want this disease to be able to pick up all the iron molecules floating around in your blood. Uh um, and saying with the TIBC as well. And the management is again treat the underlying course. Okay, so now we're talking about hemolytic anemias, and it's just classification after classification. Once you get the classifications in your head, you kind of understand, Uh, like this this topic way better. So you've got your hemolytic anemia, which are inherited or acquired. So inherited basically means that you've you've got it from your parents. You got it from your family. And that usually is a structural abnormality which you've inherited. So that could be a membrane defect such as hereditary. Uh, very cytosis. It could be a defect in the cytoplasm, so g six pd deficiency or it could be a lack of hemoglobin as well, which you might have inherited. And then you've got your required, which you can break down into immune and then nonimmune. So autoimmune basically means your body is targeting your own cells. Um, and that can be warm or cold. Hemolytic anemia as, uh, a low immune is basically where your immune cells likes amount of response to external cells. So specifically, blood transfusions is the one that I'm talking about there. And then you've got your nonimmune conditions, which is your microangiopathic huma lytic anemias, which is, uh, things like your TTP and I t P and then infections as well, which might cause it. Obviously, as you can see that there's going to be quite a lot of overlap between these conditions, and it's very hard to differentiate. Um, so again, so hemolytic anemia's think inherited or acquired Inherited has to be a structural defect. And then the acquired is things that, like your autoimmune and you're a low immune. Does that make sense to everyone? Okay, no questions so far. Uh, let me know if I'm going to quick as well. Fine. So all right, we're going onto your required huma lytic anemias, and we can break them down into intravascular versus extravascular hemolysis. So extravascular basically means anything which is not in the bloodstream. And that's specifically talking about your reticular endothelial system. And that's basically where your your reticuloendothelial system is, where you'll get a collection of phagocyte. The main sections in your body, which you've got a nice particular endothelial system would be your liver, your spleen and your lungs. Okay, so that's that's all part of that. Your intravascular hemolysis is it's destroyed in the circulation, and it's usually something which is a bit more urgent, so it will happen very, very quickly. Um, so basically, your your main intravascular causes are the ones that we were talking about before. So you've got your aloe immune response. So that's a B O compatibility resourcing compatibility. And then you've got your autoimmune conditions as well. And then you've got hereditary fair. It'll psychosis as well. Um, and then your extravascular stuff where you nobody's got enough time to actually take it to to an organ and then destroy it there. So your malaria g six pd drugs PNH as well p NHS paroxysmal nocturnal hemoglobinuria Um, the way that PNH usually presents. I think looking through the past papers for a path, I think it's only been asked once and the way that it presents as you get hemoglobinuria in the morning. Um, and as a result, you get low. Think so. There's a There's a molecule called haptoglobin, which mops up loads of human globe in in the blood stream. So you get low haptoglobin and high, uh, serum H B as well, and a high ldh um hum Editori sparrow cytosis. So it's an auto zonal, dominant condition. Um, and it's basically a defect in vertical interaction of the red cell membrane. So, uh, there's loads of proteins in the red cell membranes such as Ankara in spectrum. It's basically a defect in one of those, um, the way you will be able to tell is by looking at a peripheral blood smear and you'll see these really nice round blood cells, which are very dense in color. Uh, there's no central pallor, as you would expect in a normal test. And the way that you test it is like we said earlier today. So you got the positive. It's like the osmotic fry fragility test. So yes, Uh, yes. I'm in particular is the more sensitive one. And, uh, what you'll get is this, uh, sorry you got? Yes. Yes. And more. Um a whatever you want to call it, um, a binds to, uh, plasma membrane proteins. Um, and if you're if you've not got enough of these plasma membrane proteins in conditions such as hereditary Sarah tight, it's hereditary spherocytosis. Then you're not going to get much binding. And as a result, your positive test basically means you get less binding of the dye to that red blood cell. Your osmotic fragility test is basically you put all these red blood cells in different concentrations of, uh, saline. Uh, depending on the specific dilution that you use, you'll find that, uh, these red blood cells tend to disintegrate much more quickly compared to a normal red blood cell. Um, and the management will be with folate supplementation and then later on the splenectomy. So in that first question that we talked about, there was a The father had a splenectomy, so it's probably hereditary spherocytosis as well. Um, I wouldn't go too much into the details of which protein. Uh, okay, so would thalassemia come under Huma Lytic anemia? Um, it depends. It depends on the cause. So often. What you'll have is with thalassemia in particular is if your red blood cells are really crappy. Your your body tends to take them away to things like the spleen, um, and will destroy them. So, yes, you would get, uh, early stages of the disease. You get a, uh, extravascular hemolysis iss later on down the line when your spleen just becomes less functional because you you have to get rid of all these blood cells all the time and these crappy blood cells are continuously being produced. You then don't get him hemolytic reaction as as much or as often. Um, but you're probably at more risk of any sort of oxidative stress if you've got any sort of hemoglobinopathy. And as a result, maybe in your lifetime you might have some humility reactions itself. So, yeah, the main point that I'm trying to make here is the positive E m. A test basically means you get less uptake of that die because it doesn't bind to as many of the plasma protein cells as we was born. Okay, G six PD. It's an X linked recessive gene. Um, it's found in about 400 million people across the link across the world, and it's thought to be protective because, uh, against malaria. So you'll find that, uh, the areas where there's loads of G six PD deficiency tends to be all the areas which are endemic with malaria, and the thought process behind that is if you've got the malaria parasite in your red blood cells, Uh, and you're you get exposed to an oxygen distress and you get rid of all the red blood cells. You actually get rid of the parasite itself, and as a result, you get less affected by it. Uh, that's the same with Byetta Thile Tray as well. You'll find that there's a lot of overlap between, um, those areas and malaria endemic areas. So G six PD just a quick, um like recap or maybe understanding of it. I'm not sure if someone's just asked a question. No, so no one's asked. Okay, so G six PD basically it's used in a pentose phosphate pathway, Um, and basically the the purpose of this pathways to produce NADPH. And that's used. So let's think it would slow this down a bit. Pentose phosphate pathway. You want to produce NADPH and that's used to require intracellular glutathione. Glutathione is something that will stop you getting your red cells getting, uh, damaged by oxidative stress. So let's recap that one more time. So pentose phosphate pathway. That's basically the purpose of that pathways to produce NADPH. Um, and that's you. Any DPH is used to maintain intracellular glutathione. Glutathione is used to protect your red blood cells, so if you don't have that G six pd, you no longer can generate the NADPH and As a result, your cell is way more, uh, likely to get stressed by oxidative stress. Um, the key thing in the questions that you'll have to see is the trigger. So is that antimalarial? So you might want to have a look at the name of some of the anti malarials because they might mention like, primaquine. Uh, sometimes they even use doxycycline as a antimalarial. So just keep an eye on those kind of things that might might, uh, make you think more towards G six PD as opposed to anything else. You can get some antibiotics causing it so sulfonamides ciprofloxacin and then your favorite things like father beans, um, and moth balls in particular can cause G six pd deficiency. And what you see is things called hinds bodies, which are these like intracellular inclusions. Uh, here. And it's a result of basically oxidative stress. So the little red dense balls Can you see my Yeah, they're, uh um And then you've got your bite cells as well, which are here, which basically just looks like a bite has been taken out of itself. Um, as a result, you get inter versa. Lumbalis issue get unconjugated bilirubin, uh, low haptoglobin is, and then loads of hemoglobin. Urea as well. Okay, so this one's a bit more complicated. So, um, I wouldn't spend too much time trying to get your head around this. It can take a long time. Uh, so you've got autoimmune. Hemolytic anemia can also be divided into warm and cold, and that literally means the temperature of which the antibodies will bind to the cell. Um, you just need to know that warm is mediated by i g. So your immunoglobulins, which are associated with late stage responses and, uh, cold is mediated by I g m. Which is more your acute, uh, antibodies. Uh, so things that might might show you are so cll sle methyldopa. Those are things that can cause warm. Um uh, autoimmune hemolytic anemia. And that's usually a temperature above 37 degrees. And then cold is usually a temperature between 28 31. Uh, warm tends to be way more severe. Um, I don't know why, but it just tends to be the case, and then your dat screen. Your direct antiglobulin test is basically where you, uh, put in a, uh, anti globulin against the antibodies that are binding to your red blood cells. Um, and the way that you treat it is steroids. You can say steroids for most anything in fifth year, and you'll probably have a correct answer. Um, and the treat underlying cause and then rituximab itself again. You'll get all the slides so you can have a look and try and get your head around these kind of things. Um, I wouldn't spend too much time thinking about the difference between warm and cold Autoimmune hemolytic anemia. Just remember the temperature and the antibody associated with it. Okay, so non autoimmune hemolytic anemia, your direct antiglobulin test that's going to be negative. That makes sense because you're not producing the antibodies against it. Um, and it's not caused by a breakdown in the immune system, and it's usually something like, uh, an infection. Or it can be something which is a structural problem. So you're getting loads of red blood cells joining together, and that's causing a lot of shearing of red blood cells or loads of platelets Joining together. You get loads of shearing of platelets and that produces something called microangiopathic hemolytic anemia, which will go on to so, ma ha. So basically, what you get is, uh, damage to the end of thelial surface. As you get damage to the endothelial surface, you get loads of fiber deposition on the endothelial surface, and then you get platelet aggregation on that on that fiber ring. As a result, when you're trying to push red blood cells through that blood through that blood vessel, there is less space for the blood tell to go through. And as it ends up hitting this like collection of platelets and vibrant and it ends up shearing it. So the sort of things that we'll see on the blood film of things like your schistocytes, which are basically like broken down red blood cells, which we can see um, here, these little crappy red blood cells, which aren't very circular. Um, And then you get thrombocytopenia because all your platelets are getting stuck to the vibrant. So you get loads of, um, like a really low platelet count. And the one thing that I want you to remember is that microangiopathic hemolytic anemia is a syndrome, and it's a It's a collection of symptoms which is caused by three main things. We've got hemolytic uremic syndrome TTP so thrombotic thrombocytopenia purpura and disseminated intravascular coagulation. So again, Maha is the branch term and all three of these things cause Maha Okay, so in that question that we asked before you are correct to say, Maha, but there's something in the stem which point you towards the direct cause of it or something more specific. So ma is like a collective term that we use. Um, the way that you can differentiate has TTP from d i c is d i c so disseminated intravascular coagulation. It's basically where you get a massive cytokine response, uh, as a result of this cytokine response usually caused by things like sepsis or surgery, for example, or if you're really into your hematology, it can be caused by something called acute acute promyelocytic anemia, which is, I think is like a different subset of a ml, Um, so you basically get loads of the cytokine responses being produced. As a result, you get loads of coagulation, and when your body starts to coagulate too much, you lose up all your clotting factors and your fire brain, and you end up getting really high. A p t T and PT because all your clotting factors are used up. So you clot and then and you start using up all your clotting factors, and it's basically caused by a completely dysregulated cytokine response. And again, treatment is supportive. So hemolytic uremic syndrome, the one that I want you to remember is the one association with kids that we've seen probably see outbreaks of this every single year. Um, and it's you'll get a really bad diarrheal illness in a child. Um, and the triad is your microangiopathic hemolytic anemia. So you get that cytokine response, you get loads of shearing of red blood cells. As a result, you get your thrombocytopenia. So you get your low platelets, and then you also get acute renal failure. Now, the reason why this is is because usually, uh, one there's is to do with the e. Coli damaging your kidneys, but also your as a result of having all these like little pieces of red blood cells and platelets and vibrant stuck together, you can get a little emboli and then that causes acute renal failure. Um, and the way that you manage this is supportive. So you actually don't give any sort of antibiotics for this, You normally just treat it and itself results by itself. Now the problem becomes when we we don't treat it, we don't give supportive care. So they get dehydrated and you will die of, like, renal failure and those kind of things. Uh, if you look at questions, okay, No questions at all. Fine. Um, okay, fine. So TTP, uh, t g p is thrombotic thrombocytopenia Nick Purpura. So, essentially, uh, the body has a bunch of, um, like so in the in the first part of homeostasis, you have platelets binding to the damaged endothelial surface of your of your blood vessels. And when they the way that they bind to the endothelial surface is by a molecule called V W f So von willebrand factor. Now, your von willebrand factor is technically just like a single molecule. That molecule can join to multiple multiple molecules and form a huge chain of von willebrand factor which can be massive, right? It can technically go on forever. If you really wanted it to now, obviously that wouldn't be good, because as a result of having a massive chain of V w f, you'll end up like collecting loads of platelets, and they will cause a big clot. And so what your body produces is this enzyme called Adams T 13 and Adams T 13 Cleaves V W F chains that specific sites to stop it growing really, really long and TTP thrombo thrombotic thrombocytopenic purpura basically is. When you don't have that Adams t 30 13, that enzyme and that can be congenital, it can be acquired. Usually it's acquired because you'll find it randomly in in a woman who's just had pregnancy. And then they suddenly become really thrombotic. Um, so, uh, if we break down the name so thrombotic so your your clotting a lot thrombocytopenia like you're losing all your platelets. Uh, purpura, basically, you get all these, uh, collection of V W F strands with platelets attached to it, and then they finally break off, and then they form little emboli around your body. And then as a result, you get your purpura and also because you don't have enough platelets. You also get bruising and purple from that as well. Um, so the key features are your ma ha, which we said your thrombocytopenia your acute renal failure. So those three things that we look back at hus are exactly the same. The thing that differentiates them the most of the neurological symptoms. So in that first question, when we talked about it, we said that the patient was confused and neurological symptoms can be confusion. It could be headaches. It could be a taxi s seizures. It could be anything really. And if you see that with all these symptoms, you have to think TTP uh, it's got a very, very high mortality rate and as a result, you need to have very, uh, strict supportive care and plasma exchange. And that's usually done on intensive care or critical care. Okay, the I see. So it disseminated intravascular coagulation. You've got a massive cytokine response caused by, say, sepsis, trauma, obstetric complications or malignancy. So all these cytokines are being produced As a result, You use up all your coagulation factors and you clot. And after you used up all your coagulation factors, you then start to bleed because you used them all up. So it's a very strange system because you you end up losing all your platelets. You've got low fibrinogen and your PT and aptt are high because you have no coagulation factors whatsoever. And your d dimer is raised because your d dimer is your fiber fibrinogen degradation products. And basically, your fibrinogen is completely destroyed in this process. As a result, you get a high d dimer. Um, you actually see this more often than not, If any of you guys are lucky enough to have an intensive care rotation, you'll see this a lot. And you'll find that the patient's end up starting to bleed from their mouth, they believe from any lines that they have in their neck or in their hands. Uh, and it can be quite a horrible yes, and you basically have to get rid of the cause of it. Um, and then also you can give, like, a coagulation factors. But if you keep giving coagulation factors and you've not got rid of the cause, then you're just gonna feed this process and they'll just bleed to death eventually. Uh huh. Okay, let me just having a look at any questions, okay? No question. So far, is this the right place for you guys? Do you want me to slow down? Um I don't know if anyone wants to say anything or not. I will carry on then. Okay. So, uh, with D I see you get your prolonged a ptt pt Uh, basically, all of the things get prolonged except your your fibrinogen, which gets decreased, and your platelets, which get decreased as well. Okay, so this is a nice little summary slide, which, if you don't remember anything about those different triads and those different syndromes and everything like that, Ma ha big branch term hus If you've got hemolytic uremic syndrome, think e coli Think child. Um, and then renal failure is really big One of their If you've got TTP, it looks like has, but it's also got the neurological symptoms as well. Um, and then if you've got d i c, I think that the clotting is absolutely screwed. Um, and as a result, you get, uh, coagulation and bleeding at the same time, which makes no sense. But it does happen. Uh, d I see in your own G courses in particular or in your o n g section of your specialties comes up a lot when you have, uh, say a woman who's, uh, in labor. And then she has a amniotic fluid embolus. It's often associated with disseminated intravascular coagulation stock. Uh, all good, Fine, awesome. Thank you. All right. And then this is just, like a nice summary slide of everything. Um, it's just the investigations that you might want to do in this situation. Uh, so the dat test, um, he considering osmotic fragility, all that kind of stuff, G six pd MPK You can actually just measure the amount that you have Heinz body stains, hams, tests, all that kind of stuff as well. Uh, hams test is basically it's a way of looking for that. Pyrex is more the nocturnal hemoglobinuria that we were talking about before, Uh, which is basically a lack of this protein. This, um this g p r g p l links protein. It's a lack of that, and as a result, you get your heart test, Um, and then for malaria thick and thin blood films. Uh, they'll basically look at one amount of parasitic infection that you've got. So the amount of malaria cells in your red blood cells and then the other one is to look for, uh, the different strands, uh, the different type of malaria. So faster. Parham overlay all that kind of stuff. Okay, Um, so you've got your clinical features of hemolytic anemia. You got your palate because you've you've lost all your your iron. Uh, you've got your joined this because you've got loads of unconjugated bilirubin just floating around you. You got your splenomegaly because you might be pulling it into your spleen. So with, especially with extravascular hemolysis. Uh, pigment urea, which basically means your urine becomes really dark and family history really important there, um, and then anemia or so for lab features, Anemia makes sense reticular sites. So reticular sites are basically, um, in your maturation of your red blood cells. Particular sites are very early version of that, and they usually they should only be in the bone marrow, so you should only find reticular sites in the bone marrow. Now, if you're destroying all your red blood cells in the peripheral circulation, what can often happen is your bone marrow is like, Oh, we need to get our red blood cells out, and they push these reticular sites out. And the way that you can tell the difference is that the reticular sites tend to stain a bit of a different color, and as a result you get a polychromasia so different shades of different red blood cells in your peripheral blood film, and they tend to be bigger. So if you've got a patient who's had an acute hemolytic reaction, you often find that their MCV tends to increase because they've produced loads of reticular sites. And that's increased the number of cells, uh, the size of the cells in your peripheral blood film. Um, you've got your hyper bilirubin. Uh um, conjugated bilirubin there, and you get your increased ldh, which is found in the cytoplasm of your blood cells. And then haptoglobin is something where it's a molecule, where it floats around in your blood in your in your blood stream, and it wipes up any sort of free hemoglobin. So if you've got a low haptoglobin, that's because your body's had to use that haptoglobin to mop up loads of hemoglobin just floating around in your bloodstream. Uh, anemia summary. So, just for your revision as well, remember, that's microcytic normocytic and then macrocytic. And then in in Normocytic, you can again differentiate and classify them into, uh, extravascular hemolysis and intravascular analysis Okay, so let's have some questions again. So if you guys wanna just give it a go, have a think about this one. It is a bit of a hard question. Um, these are the questions that might differentiate you in the exam and, like, push towards the more distinction star sections or for yeah, awesome. Fine. Okay, Cool. Um, yeah, it's It's up to you in this exam. Like, how much detail you want to go into and how much you actually care about this stuff. Realistically, in clinical practice, nothing ever happens. Like you won't need to know any of this information. And often what ends up happening is you just call the hematologist when you see something a bit dodge, which is a shame. But that's generally how it works. Uh, so former mutated tunes can lead to hydrops Vitalis and I'll go on to what? What that means if you don't know what that means at all. Okay. Uh, Mohammed is a four year old boy who was born in Bangladesh. Uh, he presents to your pediatric clinic. What is the likely diagnosis? And for extra marks, If you can say what the The image on the right shows, then I'll be very, very impressed. Any suggestions you can. You can put a big guess in, considering we've been over the content of the lecture. Um, might be one of the conditions that we mentioned before as well. Awesome. Fine. Jasmine, you have I see a Yeah, quick. Uh, all right. Um, he was atrocious. Nice one. OK, awesome. Uh, Hassan, like, really, really good. Um, and B to thaw. Yeah. Fantastic. So you are completely correct. It is beta thalassemia or a really bad crew cut. Yeah, either one. Um, so it's beating felt, um and this is beautiful, major. And then specifically what Hassan said was that there's a hair on appearance. So if you look at the image really carefully, what you can see is that these little weird white spiculated things. So normally your your the the edge of your skull should look like that. That's where your periosteum is, right? If you've got loads of, uh, if your bone marrow is producing loads of red blood cells, it tends to get hyperplastic. So you get an increase in thickness of your your your your bone marrow, and you get this hair on end appearance. Uh, realistically, this picture is probably taken in, like, the eighties or something, and you don't see this anymore. And I'm probably doing in this service to say Bangladesh screening program is not very good. But the point of that is that in the UK, you screen the thalassemia. It's a condition that should be in your in your good three test where you do a spot time like you do the prick and then test all their blood for different things. Um, okay. Peter thought Okay. So what is the best investigation to diagnose? Peter thought. Uh, okay. Okay. Can you go into more detail? Of what type of electrophoresis? It's a specific type. Um, and I know that they're quite anal about these kind of things. Um, especially for hemoglobinopathy. So they'll ask you this question and you're expected to know all the component parts of this. Uh, they weren't very nice with the way they mark this exam. They might give you, like, a half mark or something instead. Um, it's a type of electric recess, but what type of electrophoresis? Hemoglobin. Electric. Yeah. Okay, fine. So it's actually a high performance liquid chromatography um, it's just something that you need to know if you really want to go into it. If for those of you do the NBS see, you'll find that you probably did quite a lot on this as well. Um, essentially, you're looking at how long a molecule of hemoglobin is and how well it gets. Uh, this sounds quite bad, but how? Well, it's retarded by the gel that's used. Um, and that is the word that they use are not being politically incorrect. Okay, hemoglobin office. Um, so basically, um, hemoglobin, you've got, uh, four globin molecules and then one he molecule in the middle. The molecule is your little iron molecule. And there are different types of hemoglobin that you can get depending on where you are in in your lifespan. So when you're a foetus, you have. So you've got your full glass globin molecules. So, um, if we just take a second back, hemoglobinopathy basically means there's something wrong with your global chains. Okay, so you've got your global chain synthesis, which is affected, um, and you've normally and a normal person, so me and you would probably have alpha alpha globin chains and B to globin chains. And what gets confusing is between HBA HBA to H p f and then trying to remember the Alpha globin chains and the what? Whatever goes in between. So what I want you to remember is that HB A is our default red blood cells that are default hemoglobin altogether. Okay, And that's what most of us will have all throughout our life. Um, and that's two alpha globin chains, two beta globin chains. So four in total HBA to you'll find in infants Children, and then as they get older, they tend to go away. So your HBA, too, is, uh, two alpha globin chains and two Delta globin chains. So you don't have any basic globin chains in that in that type of hemoglobin. Now most people will have a mixture of HBA and HBA, too. Uh, there are some conditions where you might get more HBA to, for example, thalassemia. So when this beta globin is not produced properly in beta thalassemia, you'll get more HBA to produced. So even if you have thalassemia tray, you'll get more HBA to produced. And then you've got the type of hemoglobin that you'll find in your in the fetus. So you've got HB F, which has got two alpha chains and two gamma chains. Okay. And as you get older, so within the first two years that gamma globin chain synthesis basically stops. And your genes, which produce that gamma globe in tend to go back into their shell and then you don't produce them anymore. This graph here shows you the types of globin chain synthesis, and as a result, you can figure out what type of hemoglobin you'll have in your body. And diagnosis is made with hemoglobin electrophoresis, which is what we were talking about before. But in particular, high performance liquid chromatography is is the actual answer for that question, uh, so disorders, thalassemia and sickle cell. So we'll talk about both of these things in a bit more detail. So try and remember this, and I'll try and come back to it a bit. Beta thalassemia is basically a problem with your beta globin chain synthesis. So in your HBA, which is our default hemoglobin, we have two alpha globin molecules to beta globin molecules. Okay, now, if you've got a problem with your beta globin chain synthesis, then you will get a problem with your overall hemoglobin molecule and how it reacts and how it interacts with oxidative stress, for example, so there are. It's a spectrum of disease, so everything in medicine is a spectrum. So if depending on the type of gene defect that you have, um, you'll get a different clinical picture. So there are only two genes, uh, two beta globin genes, one from each parent, which codes for your beta globin overall. And that's found on chromosome 11. Okay, and if one of them is defected, then you might have an intermedia or a minor picture. Or if you have a really bad defect in that one gene, then you might have a major picture. Technically, both of them are affected. Then you'll get a major picture, and it's very different, depending on which base pair is deleted or what What what mutation is is found in the first place. So all I want you to remember is Peter Thought associated the chromosome, a level 11, and you'll have a clinical a wide clinical picture. So Major is the ones that we are afraid of. So that boy Mohammed, in the first question he's probably got Major because he's got all that every through poetic Axion happening. And as a result, he's got the hair on and appearance and all that kind of stuff, Um, and that requires regular blood transfusions transfusions for the rest of your life. So it's a pretty horrible diagnosis to have. Intermediate is basically, you get all these niche types of globe in defect, and you get like a small reduction in beta globin chain synthesis. But not nothing horrendous and then minor. You'll probably find them quite a lot of the population, especially, uh, South Asian populations, or even, like, uh, the Greek Mediterranean Peninsula area. You'll find some beta thal minor as well. Um, and usually that's fine. But say if they get ill or they have an infection, they can sometimes become anemic, even if they have just minor or be to Daltrey, as we used to call it before, Um, and the management is regular blood transfusions I insulation and then folic supplementation. So alpha thalassemia. So we said that beta thalassemia was on chromosome 11, and it had two genes coding for it. Now alpha thalassemia is coded on chromosome 16, and it has four genes coding for it. So as a result, you get a largest spectrum of disease. But it sometimes can be completely silent. It can be slightly symptomatic or death. It has no chill. It kind of just goes one to the other. Um, so you've got alpha globin chains, four of them in total if you get one knockout genes. So if one of your genes is affected, but the other three are fine, you get like, a silent defect. If you've got to affected, then you you call it alpha thal tray, which is kind of similar to Byetta. Thal, uh, beta thal tray as well. Um, and if you get three, you get something called hemoglobin H, which is like, I think it's the hemoglobin. Hammersmith is what is named after. So after our hospital, uh, and then hemoglobin Barts because that was founded in Bart's. Um, and that's where you get all four genes knocked out. And as a result, that's not compatible with life. And you have death in the uterus. And that's known as hydrops fatalist. Um, management again break a level of transfusions, high insulation and folate supplementation. Any questions? Yeah, Yeah, exactly. Laura That's correct. Um, so yeah, it is a type of electrophoresis. It's just specifically for hemoglobinopathy. They'll want you to say high performance liquid chromatography. OK, sickle cell disease is actually a problem with your beta globin chain synthesis, and it's a specific mutation that causes your cells to be a bit abnormal. As such, you can get a spectrum of disease as well. So if you look at this, H B S s H p h B s all this kind of stuff, Basically, what it is saying is the type of hemoglobin molecules that you have. So, you know, we were talking about hemoglobin, a hemoglobin, a two, and then hemoglobin F hemoglobin s is the equivalent. It's just like a a sickle cell. Hemoglobin molecule. Um, okay. And the way the specific mutation again, it's pretty low yield. But it has come up a couple of times. So it's a glue to glutamine, uh, to avail mutation at code on six. Uh, and that causes your HPS. And basically, what that means is you end up getting a negative and a positive charge, and amino acids or two separate amino acids being very close together. And then they end up interacting with each other and cause the whole hemoglobin molecule to basically capsize on each other and become sick. Aled, the key features are the way that it presents. And this one is quite obvious. So a hemolytic crisis. So they suddenly become randomly anaemic. Um, and they might be joined this because they've had an intravascular hemolysis. You might have a sequestration crisis where you get extra vascular hemolysis. So all these dodgy cells get stuck into your spleen. And as a result of all these dodgy cells going in, some of your healthy cells end up going in as well. And you end up having an anemia when you actually don't have any anemia. It's just because all your blood cells are stuck in your spleen. Uh, so, ideally, you wouldn't want to give them a blood transfusion. At that point In clinical practice, they still do. Uh, but essentially, what happens is all your red blood cells. Then suddenly come crashing out of your blood out of your spleen into your into your bloodstream and you become pro thrombotic. You've got loads of stuff and gunk in your in your, uh, in your, uh, intra vascular system. Uh, you can get an a plastic crisis. Uh, so essentially, that's caused by something called parvo virus, which I'm sure you guys might have touched on in pediatrics. And, uh, parvo virus is a virus, which it goes to your bone marrow and stops erythropoietin production now in a normal person, if it stops erythropoietin production, it's not that big a deal doesn't really have that much of an effect in sickle cell disease. Where one. Your hemoglobin is already a bit crap, uh, to your basically getting your your hemoglobin has a very short half life because of how bad it is, and your body wants to remove it from the system. If you have, uh, if you have something which is stopping your red blood cells being produced, even if it's for a few days, it can actually cause an a plastic crisis. So you have no human global or, like you basically become any make you become thrombocytopenia as well. Um, and the way that you can tell the difference is the reticular sites. So with a plastic crisis in particular, you look at the reticular sites. I mean, we'll say low reticular sites. So in a normal person, if you're not having, uh, if you if your red blood cells aren't being produced very well, uh, then you would expect your immature red blood cells your reticular sites to be upregulated and then pushed into the bloodstream. Uh, in a plastic crisis, you're not able to do that because your your bone marrow stopped functioning properly. And as a result, you get this A plastic crisis. Well, uh, infections. So strep pneumoniae, uh, sepsis is really common in sickle cell patients', and then salmonella related osteomyelitis is really common as a buzzword for, um, for osteomyelitis in a sickle cell patient in peripheral blood smear, you'll see sick aled cells, Which makes sense. Um, and then the treatment is regular vaccinations, folate supplementation, hydroxyurea, which basically stops. Uh, the production actually up regulates the amount of hemoglobin. So this one hemoglobin A to hydroxyurea basically increases the amount of this human globe in, uh and that helps you have less of the crappy HPS in your blood stream. Um, OK, next question. 19 year old boy comes in with an acutely swollen knee, does not re re collect any trauma. He's not known to have any history of bleeding after dental extraction. What is the most likely factor deficiency? Awesome. But day fucked A. Yeah, really good that day. Um, So there are two types of haemophilia which we'll talk about in a second. Okay. What is the most common inherited from Ophelia? Number one. Anyone else? Number two. Okay, Nice. Very nice. Okay, very good. So this is activated protein C resistance, which is called factor five Leiden. Um, I just put that version instead because I think everyone, if you smash past, made a bit too much, You can, uh, just not actually understand what things are. And you just look for buzzwords all the time, Which is why I used to do hemostasis some thrombosis. Um, I don't know how much you want to have a quick recap on human Stasis is something that you probably will be better off having a look at in your own time. Um, essentially, you've got different sections of your human status. You've got your platelet adhesion, platelet aggregation, and then increasing of your coagulation cascade. So platelet adhesion basically talks about how the platelet sticks to the damaged endothelial cells. Platelet aggregation is the next step, which is once it's bound to the endothelial cells, how does it then get more and more platelets to come, join it and form a clot? Uh, platelet aggregation and then platelet. After all of that, you've got the the last stage, which is a coagulation, which is how can we put a nice mesh over this collection of platelets? Um, so that the blood clot stays in place because if you don't have the coagulation, you won't be able to keep the blood clot in that place into itself. So there are many ways that you can have the platelet binding to that damaged endothelial self. So the one which is direct is by G. L P. One a. And then there's one which is, uh, via one von willebrand factor, which you mentioned before, and that's using G L P. One b g L P. One B is the more common version generally doesn't tend to attach to the blood the endothelial self surface by itself. Using that one receptor, um, as a result of that binding, you get loads of release of a D. P and thrown boxing, and that causes that signals to all these platelets to then join together and then form a nice big bunch of platelets and, uh, V W f and fibrinogen. Um, and they the platelets bind to each other with specific receptors as well. So G l p t B and three A. Um, I don't think you'll need to know too much about that until Okay, so then we talked about platelet uh, adhesion. So to the, uh, to the endothelial cell we've got, we talked about a platelet aggregation, which is, well, come together. And then you get the coagulation cascade, which is separated into three separate stages initiation, amplification and propagation. And they're basically talking about how things are started off. So you've got you might throw back to the 1st and 2nd year when you talked about the the coagulation cascade. And I know that this is quite boring for you guys. Uh, but you've got extrinsic pathway, which is measured by prothrombin, and you've got your intrinsic pathway, which is measured by aptt, and they formed together to form the common pathway. Uh, the extrinsic pathway is way more common. Um, and that's because you get, um, your endothelial surface releases something called tissue factor. Tissue factor binds to factor 78 and then so and so on. I don't want to bore you with this, but what I'll do is, uh I think in the slides there's, like, a nice little recap talking about how each step works along the way. Uh, there's nothing in particular, I think I would add. And I think you're probably best off doing it by yourself. Um, so you got your Hamish Stasis and then you've got your disorders of homeostasis and then that can basically be dependent on where the problem is. So is it with the platelet adhesions to the the endothelial surface? Is there a problem with platelet aggregation or is there a problem with the coagulation cascade? So the first two platelet adhesion and aggregation are known as primary disorders. Uh, and the second one coagulation cascade is known as a secondary disorder. Um, and they basically occur because part of Verkhovna Triad is changed. So you've got a status of blood flow, you've got an endothelial injury or you've got hypercoagulability. If those three areas are not balanced together, you're more likely to clot Any questions? Sorry to digress. in path exams. Will there be a lot of what is the most Yes, Unfortunately, yes. And it's not very nice. Uh, they would in particular. They kept asking, like, what's the most common cause of this in the in the world? And then what's the most common cause of that in the UK? So even those kind of things you might want to just have a good grasp on, um, they try to move away from that as much as possible. But I don't know how successful they were. Uh, so they did tend to ask quite a lot of questions like that. Um, yeah. Unfortunately, I'm sorry. I'm not envious of you guys having to revise for that exam again. Um, okay, so Huma Stasis. So you've got, um, dysfunction in primary hemostasis dysfunction in secondary hemostasis. So secondary hemostasis what we were talking about before we're talking about all the coagulation disorders. So you've had your platelet adhesion aggregation, and then you're going on to your coagulation cascade. And if there's something wrong with that coagulation cascade, you get a problem with secondary hemostasis. So that could be hemophilia. A where you get a lack of factor eight hemimelia be where you get lack of factor nine and then you can get acquired disorders of coagulation. So liver disease or your coagulation factors are made in the liver. So if you've got a problem with your liver, you don't get enough coagulation. Uh, the coagulation factors being produced, and as a result, you get a problem with the homeostasis and then vitamin K deficiency. Because vitamin K is used to produce, uh, factors 279, 10 and protein CNs. Um, And if you have a deficiency in that, you don't get those coagulation factors and you'll bleed. Um, and then you've got your primary hemostasis, which is a problem with either the platelets joining to the endothelial surface. So with von Willebrand factor's in particular, or a quantity of defects, which is basically means a lack of platelets. So that could be I t. P so idiopathic thrombocytopenic purpura or heparin induced thrombocytopenia. So both of those causes both of those diseases caused a low platelet count, and as a result, you have a primary hemostasis bleeding disorder. Okay, platelet disorders. You can get a decreased number, uh, decreased production decreased survival, um, and then increased consumption. And then you can also get dillusional ones as well. So, uh, dillusional, you'll just basically retest the patient and then eventually, if you've, uh, usually when you'll see that is if you take blood from a patient, when they've got fluids running just down downstream on the same hand, you'll get dillusional hemoglobin and dillusional platelets. Best way to look at that is to have a look at the hematocrit, which shows you the density of platelets and red blood cells in that certain area. So, uh, that might, like, show you that something's dilutional increased consumption. So we spoke about this before disseminated intravascular coagulation. You've got your big cytokine response. As a result, you get loads of consumption of, uh, all your coagulation factors, and you also get increase in all the consumption of your platelets as well. Um, and then you get decreased survival. So, uh, idiopathic thrombocytopenic purpura, which is mostly it's immune. So you get, like an autoimmune response against your platelets and then that causes a breakdown of your platelets and increased production makes quite a lot of sense. Um, and then you can get defective platelet function itself. So, uh, it could be an acquired. So you've got, uh, irreversible innovation of your cocks enzymes, which is what aspirin does, uh, end stage. Renal failure can also cause an acquired platelet dysfunction and then congenital so thrombocytopenia. And so, uh, you will probably not need to know most of these The defective platelet functions in particular. But I want you to know their decreased number of, uh, platelets because that comes up way more often. Okay. So again, you can get immune mediated loss of platelets, so that could be connective tissue disorders. Lymphoproliferative disease sarcoid idiopathic. Um, all of these systems aren't very well understood. And why it happens, Um, and you'll find that some some conditions, such as, um, re Metroid arthritis can also cause a low a low platelet count. Uh, in particular, there's I've forgotten the name of it, but it's a It's a like a triad of rheumatoid arthritis from cytopenia, um, as well. And splenomegaly, um forgot what it's called. Uh, and then you've got non immune mediated D i, c and Maha, that's all. OK, von willebrand disease. So that was that beautiful little molecule that we have, which attaches to the endothelial surface when you've got damage to the endothelial surface and that attracts your platelets via this G l P one b receptor over here. Um, so if you've got a problem with this, um, then you're not gonna get as much clotting done very well. So the ways that you can think about it is a quantitative defect. So you the amount of V. W f you're producing is actually very little. You can get a policy to defect, so it's basically a bit of a deformed front willebrand factor. Or you can get both of them so mixed picture, which is type three. I don't think you'll necessarily need to know the different types, but it might be something that helps you understand the disease as well. The features are they have a gun surgery and they've got mucocutaneous bleeding. Um, and generally, in the stem of the question, they'll tend to make it a woman for some reason. Um, but, um, hemimelia they were trying to make it a a man because they're trying to differentiate between excellent diseases, whereas one willebrand disease is probably more common in both men and women. So it's just something that you might want to think of it if it's a if it's a man with a bleeding disorder and they've got things like him. Arthros issue might want to think of haemophilia as opposed to foreign willebrand disease. Um, so you get you could contains bleeding. Your platelet adhesion, for obvious reasons, will be less because you're not getting this. This fact is not working very well or there's not enough of it, and as a result, you play this on attaching to the endothelial surface. And like I said before, this is the main way that your platelets attached to a damaged and the thelial self. Um, you also get a reduced factory because Factor eight and BWF tend to travel as partners together. So if you get one, which is going down, you'll also get the other one going down. So it's actually very hard to tell the difference between Factor eight deficiency, so hemophilia and von willebrand disease. Unless you do specific tests, your platelet count will often be low. Your bleeding time is obviously high because you're not getting your your primary coagulation. Um, and you get a high A B T T and a normal PT differentials I don't think you'll need to know this. Bernard's Julia's Glanzmann's thrombocythemia Um, this is very, very low. You I wouldn't bother about this at all. Uh, management is desmopressin, which basically increases the amount of, um, internal or stored factor eight, and and V W f. And as because they put together, you'll get a nice little increase in in, like in your body as well. But obviously, everyone has a limited amount of desmopressin of, uh, intrinsic V W F and factory. So it will only work for a certain amount of time before your body needs actual factor. Concentrate V W f. And then factor eight concentrated stuff will help as well. Um, okay, I'll just have a look for questions. Yeah. Okay, so what? Test differentiates. So with the curricula ation cascade, you can basically test for any of the factors in particular in V W f. The way that you would do it is you would test for the size of the multi murs and the V w f itself. So you can specifically test for each of those things. Yes. I'm sorry. Yeah, you're completely right. Felty syndrome is the one. I've had a bit of a brain for it there before. So Felty syndrome is the one where you get your your tried of rheumatoid arthritis with splenomegaly getting a thrombocyte a low platelet count. Uh, test Different. Yeah, OK, I'm not sure if that answers your question so you can just for each one of those molecules, um, so, uh, immune or idiopathic thrombocytopenic purpura Basically the same thing. And it's a blood disorder caused by a decrease in the number of platelets in the blood. Uh, and you can get that because you get auto antibodies which are generated against platelets. Uh, the platelets are these basically tagged by these antibodies and then these anti platelets get carried off to your spleen and destroyed um, in childhood, you can usually get I t p. And it's, uh it's very acute. So I myself had i t. P once as well. So, like, my platelet count was like 10. Um and so the hematologist was scared that it was some sort of some sort of bone malignancy, but wasn't Thankfully, it's just I t p, uh, didn't have any bleeding or anything like that associated with it, and it's very, very common so you'll have a viral illness and then you suddenly just get a really low platelet count. Um, you basically in childhood I t p it tends to be quite severe, but it's self limiting. Uh, in adults, uh, I t p tends to be chronic, and it just kind of has, like, a long lasting effect. So you you tend to have low platelets for, like, a plate that kind of 100 or like 80 for for your whole life. Basically, whereas in kids it's like you find and then play. The card goes down, and then it goes back up to normal after a few months or so. Um, so the way that you treat it i v i g So you're basically trying to get rid of all those antibodies in your bloodstream Splenectomy. So you're stopping all the pooling of these platelets. So even if they're tagged by these antibodies, they can't be taken off to the spring and destroyed treatments steroids, because again, steroids work on everything. Uh, they basically affect your lymphocytes in particular, which is why they work with so much stuff. Um and okay, hemophilia? A. Like I said before, it's excellent recessive, so you'll often find it in men more than women. You can get it in women, but less likely to happen. Uh, factor. Eight. Deficiency is what it is, Um, and you'll get spontaneous bleeding into your joints. Um, and you'll get a high A p t t. Um, and you It's way more common than hemophilia. B. Uh, you can't tell the difference between hemophilia and be clinically, but the management is relatively the same. You just replace the concentrate so you replace Factor eight or you replace factor nine in particular. So, uh, there's one thing that you might want to be aware of if you keep giving exogenous factor. Eight of exogenous factor. Nine. What can often happen is, um, you produce antibodies against these factors. Um, and your your basically, you're you'll find it with a lot of hemophilia. Patient's is they've had so many doses of fact to concentrate that they produce these inhibitors, and so it no longer becomes functional, which becomes very problematic because then you can't really treat it as well as you would have been able to before, Um, vitamin K deficiency. So like we said before, you need vitamin K factor 279 10 protein C and protein s. Um, um and you basically can get it secondary to malabsorption or warfarin use or antibiotic therapy in particular. Um, and factor seven tends to be the first factor to be depleted. And that's often a question that they ask him the exam as well. So factor seven. Shortest half life. And is that the first factor to be depleted overall? Um, so you might have someone with liver disease who's got problems with coagulation, and the reason why is because they've got, uh, low vitamin K as well. Um, I know you can treat it with both PCC. Basically, uh, any questions? Okay, No factor. Five light. And so this is your deficiency in activated protein, so you get resistance to activated protein C. So protein C basically is an auto coagulant, so it increases the the anti sorta anticoagulants, and it increases the amount of, um, factor five and factor eight breakdown. Uh, so you've got this thing called the prothrombin is complex, which is a mixture of your factor five and a factor eight. And your protein C is a natural way of stopping that from working. And when that stops working, your your body is less likely to to just keep clotting basically. So now if you've got a deficiency in that in that protein or the activated protein C, or if you've got a resistance to the activated protein C, it means that you're more likely to to to closet in the process, because you're no longer breaking down that that complex between Factor five and factor eight. Uh, and the way that you treat it is long term anti coagulation, anti thrombin. It's again, it's another. It's another natural anti coagulant, and, um, the way that that works, is it It targets thrombin so factor, too, Um, and then factor 10 A as well is the two that is specifically, uh, targets as well? So if you have a deficiency in that that molecule, uh, then you're more likely to clot. Um, and you tend to get really weird types of clots so you'll get like a splenic or a mesenteric one. Or you can often get like a really large, saddle shaped pulmonary embolus. Um, which, um, is is pretty heavy, and you'll also get it. It tends to be in really young patient. So if you find a young woman, for example, who's had a P and they've not really gotten any risk factors at all, it's probably a good idea to test that anti thrombin. I I think it's one in every 2000 people is about how common it is. Um, and you can also get a congenital or acquired. So there was actually a few cases that they noticed associated with the covid vaccination. So it gave you an acquired antithrombin deficiency, and as a result, you're more like to clot protein senior protein s deficiency. This is really boring. I'm sorry. This bit, um So, uh, the one thing that I want you to remember with protein C and protein s deficiency the big buzzword is it causes warfarin induced skin necrosis. Um, and basically, I have no idea what the actual mechanism is of that. Um, just remember that it's associated with the skin necrosis. And again, you'd want long term anti calculation. Uh, fine. No questions so far. Uh, do you guys want to give this a go? We're nearly done. So we'll whizz through the last bit. I know that you guys are probably shattered. Yeah, awesome. Fine. Really good. Well, sub ca low molecular weight happened. Uh, the reason why we don't use anything else is one warfarin is teratogenic. Uh, so no go. Definitely. And then doe ax, which we are using now just has no evidence base behind it as of yet. Just because we don't want to really try anything unethical. Now, when we know, learned elective the weight happening works. Um, we've got which which of the following is low during pregnancy. So this section, in particular not very high yields. I'll whiz through it really quick and then go into the blood transfusion reactions, which you might find a bit more useful. So if you guys want to give that a go, Any takers? Three. Yeah. Awesome. Really good. Okay, so it's protein, as in particular, which is low sitrick hematology. Basically, you've got someone who's much bigger than usual. Lot more serum fluid going around, and you get volume expansion. As a result, you get a dilution, all anemia. So your actual number of hemoglobin cells are probably the same as someone else. But it's just dilution because you've got loads of fluid going around it. you got thrown beside Apia near as well, which tends to happen in most, um, most women as well. And depending on when it is, you'll have, like gestational thrombocytopenia or more serious causes depending on which part of the pregnancy that occurs. You're basically a much higher risk of having a clot when you're pregnant, because as we'll see in the next slide, you get an up regulation of loads of your your coagulant factors and the down regulation of your anti coagulant factors. So this is something that you might just want to have a look at. Uh, generally all your clotting factors go up your natural anti coagulator and anti coagulant protein s does go down as well. Um, and as a result, you're more likely to clot. Okay, um, humanistic disease, um, of the new of the foetus and newborn H d F M. So we'll try and go over this really quickly. Uh, so this is probably something that you might want to know about in your in your obstetric examination as well. Essentially, what it is is you've got a woman who is resource negative. Um, and they get sensitized to recess positive blood so that could be through. Surgery could be through blood transfusions. And when they're sensitized to that resource positive blood, they then start to produce antibodies against resource against resource positive blood. Now, that's fine. On the first time that something happens. The first sensitization event, nothing acute ever happens in that first one. Now, when that becomes a problem, is, for example, if a woman has a their recess negative and their child is recess positive in that pregnancy, it's usually fine in the next pregnancy. If they have a recess positive baby again and there there are obviously still resource it anti. Those maternal antibodies will then destroy the red blood cells in the new foetus and as a result, kill the baby and you get hydrops fatalities, which is why we need to prevent the sensitization events. We stop the antibodies being produced in the first place and we give anti d uh, I G um and we give that 28 weeks and then 72 hours of a sensitization event so that can be like amniocentesis and all those kind of things you want to give it then as well. Um, so if that makes sense. So you're the way that you want to think about is a recessed positive mother the first time. So, like the woman is sensitized, nothing happens the second time you get an I G mediated response. So I g is your your long term chronic response And that happens the second time. Does that make sense? So we need to stop that happening. And by by the way we stop, that is by giving, uh I g uh I'm sorry, I v i, g, um, help syndrome. So it's basically, uh, in preeclampsia. You have a spectrum of disease. So preeclampsia being high BP, high proteins in in in the urine as well. And then it becomes eclampsia where you start to get, like, neurological dysfunction so you can get seizures, Um, and then another way or another part of that spectrum, something more help syndrome, which is where you get him. Al icis, elevated liver enzymes and low platelets. Uh, it's a completely life threatening. You get the features of that maha that we're talking about so technically, in that diagram, we should have put Maha um leads to T T p D. I C. Help and H u s as well. Uh, so these are all things that you might want to have, uh, involved in the thing, Um, alcoholic fatty liver disease of pregnancy is, um you get much higher, uh, liver enzymes being produced as well in that disease as opposed to help syndrome. Um, so the best way to manage this is to deliver the foetus itself. Okay, so this is the last set of two questions, and then is the last topic, and then we're done. So if you just bear with me, and then we'll be done really quick, and then you can ask any questions that you want. Okay. What can we say for for some nonhemolytic transfusion reaction? Yeah, pretty good. Okay, So physical blood transfusion the ones. The parts of the question that I want you to remember he feels for your British, but his temperature is fine. Uh, his heart rate's fine. His blood pressure's fine through to rates finals. The oxygen saturations are also fine. So that's what you will point you towards nonhemolytic transfusion reaction. Okay. Um, so he's 40 year old man involved in a major trauma receiving a blood transfusion in hospital within 10 minutes of the transfusion, he becomes acutely unwell with fever. That's meant to say Reichel's not regoes. Uh, and significant abdominal pain. So observation. So his tachycardic at 100 and 20 for his BP is slightly bored. Line kind of hypertensive. Uh, his oxygen saturations are fine on rumor. Uh, his respiratory rate is 24 his temperature is a bit high, actually. So what is the cause about bear in mind the time anyone want to give it a go acute hemolytic transfusion reaction. Awesome. Fine. Um, let's have a look at that. Good. Okay. And then the last question. So 63 year old inpatient gastro, uh, admitted for upper GI Bleed. Uh, has become short of breath after a transfusion over the last 20 minutes. These heart rates okay, respiratory rate is high. BP is low oxygen saturations are low, temperature is high. Um, and he's got bilateral inspiratory reputations. His heart sounds are normal. His JVP is not raised. He's got no rash or swelling. Patient's completed a blood transfusion of one unit. Um, two hours ago. What's the most likely reaction? Two awesome trolley is what this is called Transfusion related acute lung injury transfusion medicine. Okay, so the best way to remember this is the timeline. So the first one you'll get is anaphylaxis, That is, in seconds to minutes. Then the next one is in a few hours. You'll find that you get federal nonhemolytic reactions, bacterial contamination and then a b o compatibility. So ab Oh, compatibility. The way you're gonna differentiate it from the other two is because a b o compatibility you get the hemolysis. You can often get abdominal pain. You'll get jaundiced. Uh, you'll get, uh, Palo all these kind of things. Bacterial contamination. You're probably going to get a bit of a rise in your temperature. So it's very hard to tell the difference between these two unless you do a blood culture, for example. Um, and then later on you get these two bad boys, which are very hard to differentiate clinically transfusion related acute lung injury and transfusion associated circulatory overload. So and then you've got graft versus host disease and delayed hemolytic transfusion reactions. So anaphylaxis. So the reason why that occurs, it tends to occur within minutes, and it tends to occur in i g A deficient people and the thought process behind that is you've got an I g A deficient person. And Fairmont these are all, uh, high yield stuff in the green IGA deficiency is associated with anaphylaxis and blood transfusions, So I g a deficient people tend to produce antibodies against I g a. And when you get the i g a running around in your blood products, they tend to react. And as a result, you get an anaphylactic reaction. Uh, ab oh, incompatibility. It's an acute hemolytic reaction, and it's usually I g m related, uh, and you get intravascular um, Alice iss. Uh, bacterial contamination is most commonly associated with platelet transfusions because of the temperature which platelets are stored, which is usually about four degrees. Uh, and so it's like quite a nice pool for bacteria to thrive in. Um, you've got febrile nonhemolytic reactions, which basically means that the rise in temperature is less than one degrees. Um, and the thought is basically it's caused by antibodies reacting with white cell fragments in the blood product, causing a cytokine response. Um, so that's the main thing. So it's It's a very minor reaction. Um, transfusion associated circulatory overload. So Technically, what happens is you get pulmonary edema and fluid overload. So the difference between so you've got transfer, transfusion, associated, circulatory overload and then transfusion related acute lung injury. So with the overload, you'll get signs similar to heart failure. The similarity between the two is the bilateral pulmonary infiltrates. So both of their chest X rays look terrible. The difference between that is the taco often looks like heart failure. So you'll get a raised JVP Uh, and you'll get a hive bp. Um, and basically what ends up happening is, uh, if you give them frusemide, they react really well and they get much better. So the same way that we treat heart failure, we can treat taco and you'll get a reaction to the furosemide being given. And you can pay out all your your all the volume inside of your blood. Transfusion related lung injury is basically where you get white blood cells from the from the donated blood getting stuck in the pulmonary capillaries. As a result of all those white blood cells getting stuck, you get basically a release of neutrophil protea, a lytic enzymes and toxic oxygen metabolites, and that causes your your your alveolar right to get destroyed and you get a lung injury. We don't really quite understand the whole mechanism behind a trolley. Um, and they tend to happen about 5 to 6 hours after the blood transfusion was started in the first place. Delayed hemolytic transfusion reaction is I g g mediated. So the first one was I GM mediated. This one's I g G mediated and occurs within one week. So they go home after having blood transfusion and they suddenly look really yellow. Or they suddenly have a really large spleen or something. About then you would think that this is extra vascular hemolysis associated with delayed hemolytic transfusion reaction. Graft versus host disease is essentially where the white blood cells in the donator in the donated red blood cells attack the host normal cells. Does that make sense? And you get basically attacks specific area, so you get attacking of the gut, the liver, the skin and bone marrow. So often, the first sign of graft versus host disease is diarrhea, for example, and you'll see that in like, say, stem cell transplants or renal cell transplant patient's at renal transplant patient's, for example, Uh, This is just like a nice little, uh, slide on warfarin reversal. Um, I don't think you'll need to know this. Basically, if you've given too much warfarin, um then try and replace it with vitamin K. If they have bleeding, then give them vitamin K and also give them PCC because that replaces all the all the problems very quickly. Uh, whereas Vitamin K will take a while to work. So the way I revised for my path exam was I did the path guides for med, the lecture series. I made loads of, uh, questions from each of the lectures and then just did them, like, 56 times when over the course, lead lectures, loads of times, uh, and then went over the hematology and I d sections in past med. And if you can find these flash cards, I still can't, uh, right to the other day. But if you can find this girl, she was two years above me. And flash floods are amazing. Um, if you can find them, then they'll be really good. Uh, and if you have time, please, can you fill out a few platform? Um, thank you for paying attention. for their along. I know it's quite hard. That's my thing. Do you have any questions? I'll have a look at the chat now. Richie, thank you for the lecture. That was That was really great. Thank you very much. No, sorry. It was really long. It's okay. I thought was a good pace. Actually, I think everyone's able to follow, which is quite nice. I've posted the link for feedback on the on the chat. If you if you just stop showing screen riffing, then I can share my screen people to get access to our feedback form that can give to you as well. Yeah. Done. What's up? Do you have any questions, guys, if you just post in the chat There you go. Have you guys just got my QR code there? That should be a link to the feedback. I don't think we have any questions at the moment. Um, so the slides will be uploaded, Guys, hopefully by the end of the week on to medal and our website and yeah, uh, sorry. I don't know if I said this was not involved. Muted, but the flash cards for, um, the ones I was talking about before were on brain scape, Not on monkey or, uh thank you. Well, if no one has any more questions. Thank you very much, Russian. And thank you for everyone. Uh, coming today. Uh, take care, guys. Well, have a lovely evening.