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All right. Hello everyone. Um And welcome to the first webinar of our new hematology series at mind the Bleep. Uh My name is Delphine and I along with Sarah, the hematology leads at mind the bleep. So we are going to be lucky to have um Doctor James Clark. Uh he's a post CCT hemophilia research fellow at the East Kent University Hospitals. Um He will be speaking to us today on clotting. Um This is an incredibly important topic and something that one encounters every day as a junior doctor. So it's something really important to get your heads around early. Um Please add any questions during the talk to the chat and if time permits, we will ask James to go through these at the end. Brilliant James. Whenever you're ready, you can thank you. Thank you, Darin and Sarah. Hi, everybody. Um So I hope that you can see me if there's anything problems, please do flag up halfway thr uh whenever there's any issues. So I wanted to spend some time today just going through the very basics really of clotting cos it's something that I think lots of people come out of medical school er, when they hit the, the shop floor being very unsure what's actually what actually matters day to day when it comes to patients and also when things get a little bit more complicated what they should be doing to, to address that. So I want to sort of tackle that in a sort of systematic way. So the first thing I wanted to look at was the very basics really of this, a recap of how clotting occurs and what the processes and sta stages are and then move forward to understand a little bit about that scary clotting cascade. And then a sort of assign that a little bit to the clotting test that we do most frequently on the clotting screen and then use that to tackle some basics and then hopefully it some more complex cases going forward. Um And hopefully that will give you a decent understanding of uh how useful a test it is, but also how, how to tackle it when it, when something comes up abnormal. So when a clock forms, um there's lots of stages, surprising number really. And the first thing that happens is that when there's we talk about sort of um vessel wall injury or tissue injury, there will be vasoconstriction or vascular spasm, um sort of dealt with by nitric oxide um that stops blood flowing or slows blood flowing to that area to limit hemorrhage. And then there's this thing called primary hemostasis where there's the formation of a platelet plug and that happens in a few stages. Um The first thing is where platelets which are going round circulation in here to the damaged endothelium. So the vessel wall that's damaged and then they activate. So they, they degranulate, release their cytokines and everything else and activate, changing their straight structure. And that allows platelets to stick together. And that forms a platelet plug through platelet aggregation. And after once that platelet plugs in place, hopefully most of the blood flow is starting to, to stem and it's now time to move forward to. So healing the a area. And that's where secondary hemostasis really does come in. Um where you have what we classically think of as a clotting cascade and it's all to do with forming a fibrin mesh, forming that safe sort of scab or whatever the word to and a blood clot um to allow wound healing and, and to, to, to allow the, the, the hemorrhage to be fully dealt with. And that has to be a really tightly regulated process. Most of the clotting cascade and everything else around it is there to keep that process in check and happening at the right place and the right time because if it doesn't, then things are really bad for the human body. And as part of that process of control, you also want a, a mechanism by which the fibrin mesh will be broken down or fibrinolysis afterwards to er limit the hemostatic process to the site of injury, but also to remove any clot and to keep the hemostasis in balance going forward. Um So that's a major components of hemostasis to be aware of. When we think of secondary hemostasis, we're increasingly moving away from the clotting cascade as that linear model that you have learnt at medical school because things in the human body are never as simple as we would like them to be. Um There's lots of cross linking the er sort of er feedback loops, both negative and positive inhibition er and promotion, which can be really sort of entwined and difficult to disentangle. But in summation, we're moving to this cell based model, which is all about this process of thrombin generation. Now thrombin is factor two and basically activates that process of fibrin to fibrinogen. Uh but it's about keeping that in check. But we will for today because it's handy for understanding the tests that we do. We're gonna go back to the classic clotting cascade to help us understand what those tests may indicate as a sort of a structure for moving forward. Now, when we look at this, I think most people put their heads back in horror at the thought of it all because it's a bewildering complex of Roman numerals and numbers and everything else. And it's just, it's just unfair really, isn't it? It's really bizarre and it really is a sign of the historical precedent that we have and we have to work with to understand the body of work that's gone before. And they were named in order of them being found. Um And things were removed over time when it became clear that they were something else. So you may notice that there's no factor four and no factor six because it's understood now that this process happens on a phospholipid bilayer on the surface of platelets actually. Um And that's factor four. And then there's also the fact that calcium is heavily involved in allowing the process to work as you can see from this diagram. And that's factor six. So, you know, it's a really unfair thing to get your head round, but unfortunately, we are stuck with it. So to a large extent, we have to sort of bear with it. Um And then we can move forward to, to understanding this pathway. Now, at the bottom, we can see thrombin being two and is activated two. And that is what allows fibrinogen to go to fibrin and form that pulverized fibrin mesh. Everything else is about keeping that under control. So we're gonna start on the brown side, the right hand side here, the extrinsic pathway, which is always useful to think about cos that's where the outside injury comes in. And what we're saying there is that there's injury to a vessel wall to tissue and tissue factor is released. And that is what gets the ball rolling, activate, it gets activated seven to start working to activate the common pathway. So 10, 52 and you get your fibrin mesh. And importantly, there, the only thing that's really involved other than tissue factor, which is the propagation is factor seven. So there's only one real one involved exclusively in the extrinsic pathway. And factor seven has the shortest half life. It's the first thing to be degraded when people are unwell because it, it's used up quite quickly. Um And it's almost always something that only goes down in consequence to something else. Very rarely do you have a person who doesn't produce much Factor seven. Um because inherited bleeding disorders due to low factor seven disorder, levels are almost universally recessive and con and confined to very small areas of the world. So it's very rare to encounter a congenital or inherited factor seven deficiency. So when you've got a, an extrinsic pathway defect, it's almost certainly gonna be, you know, a medication or a situation that the patients in. And then we move across to the other side, which is a lot more interesting to hematologists because it could, it's where all those inherited bleeding disorders come from really as that side of things. So you can see at the top, we've got the, and we call the contact factors right at the top, which are um somewhat to do with the activation, we'll come back to those later. And then you have the sequence of 12, activating 11 factor nine. Now 12 isn't really involved in that cos it's can be activated in other ways. So 12 is not normally something that we worry about too much, but we've got factor 11 activating nine, activating eight with um Von Willebrand's, Von Willebrand's. And then that activates the common pathway we always talked about gets the thrombin burst and you get your fibri. So it, it is when you break it down, quite straightforward to understand and to understand that factor 13 is its own thing and we're not gonna retouch on that today. Cos it doesn't actually alter our clotting test. It's its own individual thing and that's more going on history. OK. Um And fibrinogen is obviously a key component of all this. We'll come on to that shortly. So when we're trying to tie in our test, this is very much a cascade built around the testing that we did, there was a huge amount of history to all of this and a lot of it comes down to the drugs that we use. We actually developed tests such as quick test, which then became er prothrombin time, which then became an er, an I nr mainly to monitor stuff like warfarin to monitor the effects of drugs. And then they've been used over time to understand other aspects of things. We'll talk you through how they work today and the PT and when you look at a clotting, when you take a blue top bottle and you take, send it to the lab, you'll get a common panel of things back to you. Depending on what you ask for. The most common thing will be a prothrombin time or a PT, which is looking at the extrinsic pathway really. But alongside the common pathway factors and it's a really straightforward test. OK. What we're basically doing is trying our best to simulate the body to assess, you know, secondary hemostasis at that level. So what we're doing is we're getting the plasma without platelets. So we're ignoring primary hemostasis completely and we're just getting the plasma, which is chock full of all those factors. And we then giving tissue factor, which you may recall from this diagram here is the activator of the extrinsic pathway. And the extrinsic pathway is much more keenly activated than the er intrinsic pathway. So when you have tissue factor, the only thing that you'll really get a measure of is the extrinsic side and then you add in something else to emulate the human body. So you add in some phospholipid, so the plate, so a surface to act on, you emulate it further by incubating the entire thing at 37 °C or body temperature. And you add in calcium. Now, the reason you've done that is when you take the blue top bottle, you have calcium, you have a citrated tube which immediately as soon as the blood hits that it leaches all the calcium out of that sample. And without calcium, the clotting cannot happen. So it halts that process at the time that there's a sufficient mixing of those. And that's why the lab are so keen that the blue top bottle is filled to the right line. Because if you have too much blood, then there's too much, there's not enough calcium and you'll get a, an alter, altered, altered test result. And if there's too little, you get a similar artifact. So that's why the lab are very hot on saying it's not been filled correctly. We can't run it because they know if they run it, they'll just get a really spurious result for you. It'll help no one. So they have emulated the human body. They've got the plasma, the tissue factor, the phospholipid, and they've got it at human body temperature and they add back in the calcium, which starts the, the stopwatch again. And literally, that's what they used to do was they started the stopwatch and waited until a clot formed and that was the prothrombin time. So it's a really simple test in many ways. It's now all automated. But this is the principle of it and it allows you to look at that entire extrinsic pathway. It does rely on having factors 10, 5 and two and also your fibrinogen adequate. But it can be a good marker because if it's, if it's only the PT that's prolonged, it's normally just the fact that your factor seven is low and that can be for all sorts of reasons. So it can be, er, that you've got a Vitamin K deficiency, remembering that the, you've got a whole bunch of Vitamin K dependent factors. Um, and, and Vitamin K comes from the German Coagulans. So, it's been well known for a long time that K is involved in the clotting pathway. Um, so if you're deficient because of diet or other reasons, you will fail to have a good factor seven, which is a Vitamin K So it's 279 and 10, which are your clotting factors that are Vitamin K dependent. And if you emulate that with a Vitamin K antagonist such as Warfarin, you'll get a similar picture in liver disease which produces a lot of factors. Then that will also derange things. But this is both sides of the coin as well because don't forget that 279 and 10 will include both both the intrinsic and the extrinsic if you use other drugs. So, anti thrombin inhibitors, very high concentrations of heparin or some factor 10 A inhibitors. If you don't have any fibrinogen, it'll be grossly prolonged. If you have a combination, rarely factor five and eight can be absorbed together as in come together and also very rarely chromosomal and a of Vitamin K metabolism. But those are rare as hens teeth. And so it's a very simple test that tells you that basically. Um And so some people worry going the other way if the PT is very quick. So it's a, a low time that that may be significant. And normally for the pro time, it only really happens if we give them a medication such as recombinant 78, we're giving them a fake Vitamin C vitamin, um sorry, fake factor seven which will cause us shorter time because it's happening so fast. OK. And then we have the other, the uh our test of the intrinsic pathway. So this is the activated partial thromboplastin time, which is a very similar test in so many ways because we take platelet poor plasma. So we're ignoring primary hemostasis and we're just looking at secondary and this time, we don't want to get the extrinsic pathway activated at all. So we don't, we leave out the um tissue factor and we add in an activator like a contact factor such as um silica, which is the most common one. And then we do the same things we add in phospholipid, we incubate at 37 degree C and we add back in the calcium and record the cot time. Um For a simple thing, obviously, again, it's automated. And this one, if you have a pattern where the A PTT is prolonged and the PT isn't, then you may be looking at a factor deficiency and these ones are a little bit more. It's still quite rare but still can be very low if you have an inherited bleeding deficiency, a bleeding disorder. So you may have a low factor eight, you may have a low factor 9, 11 and rarely a 12, which alters your, um A PTT because it's low but doesn't actually lead to any clinically significant bleeding cos there's uh other bypassing pits. It very rarely you can have a contact fact deficiency. And that's why we test the facts if they're normal, we sort of disregard it. And then confusingly, it can also be deranged for other reasons being a clotting factor inhibitor. And what we mean by this is that there's an antibody in the circulation that's bound to this, this um the thing that we're testing here and it interferes with our test. It doesn't mean that the blood is um clotting. Uh I it is lacking as basically clotting. It doesn't mean the factors are low. It just means that something's getting in the way of our test. And that's what you may encounter with something called a Lupus anticoagulant, which is one of these acquired clotting factor inhibitors. Now, the Lupus is one of the most misnamed things. It is more common in people with autoimmune disease and it was first identified in someone with Lupus, but it's not selective Lupus. It doesn't mean that you've got Lupus in any way. And it's also not an anticoagulant. It prolongs the A PTT, but actually in the body, it's a, it's a, a prothrombotic thing to the point where, where if you have a persistently positive lupus anticoagulant and you're clotting a lot and you mean lots of thrombosis, you have something called antiphospholipid syndrome of which a lupus anticoagulant is one. and that is a very pro thrombotic disorder and it's about using these tests to try and figure out what the difference is. And if they're both prolonged, it's the same list again where it's Vitamin K deficiency or liver disease or something else going on. And if it's short ie you've got a uh a low time, then you may be dealing with an acute phase response because the big part of it is factor eight, which is an acute phase reactant, it goes up when your body is stressed. And so if you've got lots of factor eight, your A PT will actually um allow a clot to form much faster in this test. Um W one of the tests that we will often ask for when we're trying to distinguish in a prolonged A PTT, if this is a true factor deficiency or if there's a, an inhibitor interfering with our test would be to do something called a 5050 mix. And this is quite a simple test. Really, we run the A PTT and if it's prolonged, you mix a ratio of 1 to 1 or 5050 of the patient's platelet poor plasma and some reference plasma that we know has an adequate supply of factors, it's not low in anything. And if the, the lower one here, if the factors are present are low and you mix the replacement factors in from the reference plasma, the A PT when you rerun it on that mixed sample will normalize or near normalize, showing that the patient's sample was very low in the factors. And then you can do some further testing to figure out which one it is. If however, there's an antibody one inhibitor in the way, then that will continue acting on both the patients factor, but also the reference samples plasma. So the er A PC will remain prolonged. So if there's a non correcting 5050 mix, we know that we're dealing with a lupus or something similar and it's probably not a significant bleeding concern and we need to go looking down that line and it's, it sort of gives us a very different picture about what's going on with that test. There are some other tests that we can sometimes do. You may see these from time to time such as a thrombin time where we do the same test again, but we add just thrombin in and see how quickly it clots. And this is quite a good measure of quite low down the pathway. How quickly can it clot? It needs nothing above it to work. It just needs a bit of fibrinogen and everything else at the lower end intact. And so if the fibrinogen is low. If there's liver disease or there's something going on where there's no clotting factors at all from like LI D IC or cancer, then you will end up with a prolonged uh thrombin time. It's also very good at picking up heparin which will continue to act on it. So you cos it acts on two as well. So um you were you, that's a good way of distinguishing sometimes if the thrombin time is very prolonged, then you may be dealing with Heparin. And heparin is always a big worry here because lots of samples are taken from lines, uh heparinized lines or anything else. And you worry that you're contaminating your sample with a drug directly into the sample. And so we also use other correction tests that you may see um such as a reptilase time derived from reptiles. Um And if it corrects her, it basically is heparin insensitive. So it confirms heparin contamination. Other trusts use something like a 1% protamine correction or other things. Most labs, all, all labs really will have a Heparin correction test just to make sure it's not a drug causing their issue. And then that we follow quite an algorithmic approach really. When we have a prolonged PT or a PTT, which normally with a prolonged prothrombin time, we're a bit worried about a either an inhibitor or if there's a factor deficiency. And so we'll mix to a 5050 mix. And if it corrects we can think about the clinical picture cos if they're on warfarin or anything else. Um Then we got, we've got an answer. We wouldn't do any further testing. But if we don't have a clear answer, we might start thinking, do we need to start testing some factors? But if it doesn't correct, then we'll go looking for a, an inhibitor of some form. Whereas the prolonged A PT has a bit more complexity in it because we worry a bit more about drugs such as heparin causing the issue. We worry more about a range of um factor deficiencies. We worry about um things like D IC, we worry about Lupus. So there's a bit more of an algorithmic way of approaching it which is normally to check there's no contamination with a drug, do some mixing studies and go down the route of a Lupus anticoagulant or a fax deficiency or go down the route of looking for other problems like global problems or common pathway problems. Um An I nr by the way is um basically just a norm, a um prothrombin time put against an international standard back in the day when different labs were using different reagents, the prothrombin time ranges and what was normal would vary from lab to lab to lab. And if you had someone on Warfarin who was moving from lab to lab to lab, you wanted them to have a standard. So they basically put their, their ranges against an international standard and normalized to that ratio. So that's why it's called an international normalized ratio. So it's a fancy way of saying how close is that to normal so that we can compare between labs. So an I NR is only useful for warfarin and because of historical precedence in liver disease, otherwise we should be using PT and A PTT. And nowadays, almost all my labs have a very similar reference range. Um There is the impact of anticoagulants which I wanted to touch on. Um because people worry about them so much and where they affect the pathway and everything else. So the one you really need to know is Vitamin K antagonists, which is mainly warfarin, um which affects the Vitamin K dependent factors. So it's 279 and 10 and that's a mantra that you just need to know. There's a range of pneumonics out there and I'd recommend, you know, cos it does come up quite heavily in exams and elsewhere in life. We're using more and more drugs such as doap. So direct oral anticoagulant drugs like Rivaroxaban, Apixaban Dox, those the most common ones and they act mainly on Factor 10 A. That's why they've got the X A in them. Um and they affect, depending on the labs reagents and everything else. Um They affect the PT and A PT to varying lengths. And increasingly people are moving to either a pragmatic approach of. How long has it been in their system and just treating if they need to, um, and reversing if needed or using, um, specialist levels to, to ascertain. Um, what, how, how active those drugs are in circulation from a other one. That's the big tr which acts on to a, so it's a different mechanism that's on thrombin directly and it will have a grossly prolonged thrombin time. It's a good way of always teasing it out. Um, and then you've got unfractionated heparin which affects both 10 and two A. You've got low Meli heparin, which depending on the drug you've got affects 10 and two a variably. And then Fondaparinux, which is almost exclusively via the action of antithrombin. Um on 10 A and they give you a prolonged A PTD predo predominantly. Ok. So we need to sort of try this out. Now, I've got about 35 minutes to go through these examples and then some cases. Um, so I hope that everyone's on board so far. There's nothing, I hope nothing's come up in the chat if there's any problems that people are following along. Um I think it's quite handy to have an idea for common conditions and how that would present in terms of the, the range of tests that you have. So across the top here, we've got our prothrombin time, our activated partial thrombplastin time, our thrombin time and then the platelets, a blood film, a bleeding time. Now, this is a very old test that isn't used anymore at all as far as I'm aware around the country. Um And it's a fact it's a test of primary hemostasis where people used to do a little score on the skin and see how long it took. Literally a, a stop was to see how long people stopped, stopped bleeding as effective as a measure of um primary hemostasis. But it was a really rubbish test. It didn't have very little validity and we don't use any more. The reason I put it in is that about, gosh, 5 to 10 years ago when I was doing my um exams, it came up and I was very miffed about it and I have been ever since. So I en ensure that everyone is aware of what it's testing and, and how it would affect, be affected in different conditions just in case it ever comes up. And then we've got factor 89 and Von Willebrand Factor, I'm gonna go through these and then we can perhaps if it's possible have some interaction on the cases. Um But we'll see. So when it comes to ITP, this is a thing where it's called immune thrombocytopenia. Um The old, no old name was immune thrombocytopenic purpura, but we've removed the purpura a bit cos not everyone gets purpura and this is a problem purely of platelets. So the platelet count goes very low from immune destruction and therefore the, the secondary hemostasis is untouched. So your PTA PT thrombin time 89 and S will be completely normal, but the platelet count will be low or even very, very low in single digits. And when you look under the microscope, it's a diagnosis of exclusion. You won't, you'll see very low platelet numbers and possibly some very large platelets, some giant platelets. If Warfarin's on board, this is gonna affect secondary hemostasis, affecting the, the clotting cascade. So it's gonna cause your prothrombin time and therefore your I nr to be prolonged and it'll also affect your A PTT because it's a test of both of those. Um Thrombin time is normally grossly normal cos it doesn't affect thrombin, otherwise the er too much at the bottom, um the platelets will be unaffected, the film will be unaffected the bleeding time. Although this is not strictly true because obviously anyone who's on any antiplatelet can bleed a bit longer as a strict measure of primary hemostasis, your bleeding time will be unaffected and your factors would be unaffected. Heparin would normally affect the A PTT more. They can be in particularly very, very high doses. It can affect the thrombin generation and affect two, but normally it's very subtle but it can affect your thrombin time. So that's the pattern. You'd expect a very prolonged a PTA high thrombin time and then you'd probably do an extra test about heparin contamination such as um you know, the repla time or something else. And that would give you an idea of what's going on and everything else would be normal in terms of um the um ok, in terms of um when you're on a heparin infusion, you might want to do, see how strong the effect is. And so you can do an A PTT ratio. So that's followed by an R which is quite uncommon to see outside of a heparin infusion monitoring. And it just tells you compared to a baseline where you're up to hemophilia. A is a condition and it's quite again historical precedent. Hemophilia. A just means congenital deficiency of factor eight, you can get acquired hemophilias where that factor is very low because there's an an antibody acting on that. But we're talking about congenital hemophilia here and because it's affecting only factor eight, your prothrombin time is untouched, your A PTT will be prolonged. And when you do the 5050 mix, given there's a factor deficiency, it will be correctable and the rest of the tests will be normal apart from when you do a direct test of the factor eight level, and that will be low. And then hemophilia b also known as Christmas disease, a good time of year um is the same thing apart from its affecting factor nine and the same pattern occurs with the re the relevant factor being low TTP or um thrombotic thrombocytopenic purpura. Another um sort of historical remnant is a very scary diagnosis. It's a hematological emergency and in this condition. It is um er where there is um or come to it later. A um m very a a deficiency of an enzyme that leads to very long multi of strands of something called Von Willebrand that clogs up the microvasculature. So all the cells going through the red cells get shown to pieces. So you get lots and lots of fragments everywhere. Um And that cons and that process also consumes pla platelets. And there in that court, those clumps of thrombotic material can cause stroke, heart attacks, renal failure and death normally within 24 hours or to 48 hours in about 90% of cases. So it's definitely something to go on top of, but it doesn't affect secondary hemostasis. So the clotting screen is untouched, but the platelet count is very low and there's fragments and the bleeding time would be prolonged in that condition. Von Willebrand's disease. It's a bit unusual in the sense that this is Vom Debra's is the linchpin between platelets acting and also factor eight working well. So this is a bit of a mixed picture between primary and secondary hemostasis. And it depends on how low the level is, but you can get normal clotting screens. Um And so the PT and the PTA PT can be normal, rarely, it can be um prolonged or it can be in, in more extreme variants. The platelet count is normally normal except some subtypes where the platelet count is is lower, the film will be normal. And because it's uh it's involved in the primary hemostasis, the bleeding time is prolonged. And then Von Willebrand has such a close interaction with eight that, that's normally a bit low. And the Von Willebrand's factor is very low D IC or disseminated intravascular coagulopathy is a condition where the entire process has gone out of control. So, clotting is happening without any feedback loops, it's just happening in an uncontrolled fashion. So all of the platelets and all of the clotting factors get consumed where the body's got that activated, leaving to causing clots in some areas and then in everywhere else, there's not enough platelets or factors to go around. So you end up with a coagulopathy alongside sometimes a thrombotic predisposition. And normally this is because there's an uncontrolled inflammatory condition on board like sepsis or cancer. And so the clotting screen is grossly deranged. The platelets are low, everything has gone wrong. The fat levels are very low cos everything's been consumed. Um And that's my old professor said this used to be death is coming. It's a uh a very poor prognostic sign. OK. Right. Um I don't know quite how we're gonna, I think can people come from the chat or um do, should I just go through the cases? And as an example. So I think they can contribute through um text on the chat as far as I'm aware, but I don't think they can turn that audio on. No, that's fine. Um, why don't we go through the cases then rather than asking people to type, but perhaps if there's anything that's not clear from these cases or if there's cases that they've had, er, cos, if I, if I rattle through them we should have some time for some extra questions at the end. Um, perhaps they can talk about cases that they've seen and how that was interpreted so that we can understand those. Yeah, the case one is a fairly standard one, from my perspective, where you have a three year old girl who's been referred to the hematology clinic with a history of easy bruising. And obviously, you want to get a measure of the full history and examination because Children bruise all the time because they're very active. But equally, if it's disproportionate bleeding, then you might want to assess them using something like a, a bleeding assessment tool of which the International Society of Thrombosis and Hemostasis. The I SDH has a bleeding assessment tool or a bat, which is quite good at picking up some some disorders, particularly von Willebrand disease. And so you want to assess both primary and secondary hemostasis. So looking at primary hemostasis, you look down um you do a full blood count and as a normal count and you look down the microscope as well because rarely if the platelet count is good, there might be something wrong with the way they work. So they might be very big or they might not have any Granules or some other mark marked defects, but they look normal. Um And then you want to assess secondary hemostasis as a rough and ready measure. So you do your clotting screen and that shows that the PT is normal at 11.5 but the A PTT is 45. Now, this again gives us a quite a clear history. We've got an A PTT that's quite prolonged. So it's an isolated intrinsic pathway defect here. And so we're thinking, has she got a factor deficiency or has she got some sort of inhibitor affecting it? Cos she's not as far as worse, she's not on any drugs sound likely. So we do a 5050 mix and that shows this correction which means there isn't an antibody or inhibitor getting way of the test. So we're not gonna go down the route of a Lupus anticoagulant, which can also sometimes present with stuff like bruising um with looking for a factor deficiency and she's a girl. And so hemophilia A and B are on the genes for those on the X chromosome. So you normally have to be a, a boy to be affected because you have to have an xy chromosome. Um or so, in that circumstance, we're thinking that if she has is genotypically female that we will have someone who um is likely not to have a factor eight or nine deficiency and the most common bleeding disorder in Caucasians. And we didn't actually say what her he was. But even globally, the most common disorder is Von Willebrand's disease. And so we're thinking that one. So we're gonna do some extra tests. We're gonna check a factor eight, which is a little bit low but definitely not as low as a Von Willebrand factor antigen at the activity. Now, when we do Von Willebrand's testing, it's quite complicated for diagnostics. Cos there's lots of different types. There's type one where the total number of them where around is not being produced very well. There's type two where it's been produced, but it's not very functional in different ways. And then there's type three where it's virtually absent and this is where you have basically AAA severe hemophilia type picture. In this case, we are thinking that it is low. So the number of 1 mg in terms of its you know, ratio is 20 the normal thing would be 50 to 100 and the same goes for all of these results, normal would be 50 to 100 and the activity is also low, but at the same level as the deficiency. So we think they are deficient in one with a brand factor. And so this would be consistent with a type one. So a low form with a brand antigen um called type one form Willebrand disease. And it's low enough that she probably will need some help with any procedures. If she has any accidents or injuries, she'd need some support and she may need some further help if she has uh in, in sort of 10 years time when she starts having periods. So you need to plan for all that and that's why she'd be registered to a hemophilia center, um, and be managed for a long for her life long, um for Von Mie Brand disease, we're gonna move on to case two. If you have any questions about type case one, do let me know and we can cover those at the end. Ok. So case two is a bit more of a scary case. We've got a two week old infant who's presented collapsed. So, um you know, unconscious, not responsive and they're rushed into hospital, gone straight to A&E and the pediatricians who see on arrival, ha So if you realize that they're not, the baby's not breathing and they're gonna intubate to support the breathing, still alive and they rush down to act and they show a large intracranial bleed and they, we want to assess both primary and secondary hemostasis. We do a non platelet count. So it's likely not to be that. Um but the PT is 45 and the A PTT is 50. So this is both an extrinsic and an intrinsic pathway. So it's unlikely that this is something like um you know, severe hemophilia or something else like that. This is this is combined in both pathways. It could be a very rare disorder where you've got a combined thing. So a five and an eight or a common pathway defect, but those are very rare and common things being common. You're thinking this is something acquired. And in this age group, we'd be thinking along the lines of the Vitamin K dependent factors because babies when they're born, um because Vitamin K is meta is largely metabolized and absorbed through the evolution of of gut flora. And babies don't necessarily have a huge amount of that. So it takes a while for Vitamin K levels to normalize as a result of that finding um U universally in the UK um when babies are born, they are offered Vitamin K injections to try and boost that to reduce the risk of something called Vitamin K deficiency bleeding um which used to affect about five and 10,000 and now is incredibly rare thanks to the use of Vitamin K Um but it still crops up from time to time. Um partly because patients refuse or it's not given for one reason or another. Um er and so we go looking for the characteristic Vitamin K dependent factors. So 279 and 10 and in this baby, they're all low. So this will be very characteristic of Vitamin K deficiency bleeding. Um and is, you know, not, not, not all that uncommon in hospitals. It's still quite rare but um cops up a few times per year. So we give the case three. This one is another newborn infant because lots of disorders of um hemostasis occur quite early in life. You, it's unusual to get someone presenting with a hemophilia or some other significant bleeding disorder at the age of 84. So a newborn infant is reviewed on the postnatal ward at 12 hours of life because they've got some, some prolonged breeding from a heel prick. They were having some sugar levels done just to monitor them. Um It's an egg donor ibs pregnancy. So they weren't known to have any family history of an note. Um And when they were reviewed, their, their head was quite big and they were having periodic apneas. So they a full blood count was done, which did show that there has been some blood loss or anemic, but the platelet number is normal. So we're not thinking this is primary hemostasis. We're thinking this is the secondary hemostasis area. And when we do the clotting factors, they're really grossly prolonged. So the PT is plumb normal at 12, but the A PT is very prolonged at 100 and 20 the fibrinogen is normal. So we're thinking again that we're looking not at the extrinsic pathway, not really at the common pathway cos it's an isolated intrinsic pathway abnormality. We might be thinking this is a fact 12 deficiency, but we've learned already that that isn't associated with a significant bleeding phenotype and this baby clearly is probably having a, a major intracranial event. So we're thinking this is either factor 11 deficiency, factor nine deficiency or factor eight deficiency. I didn't tell you this is a boy. So they could well be affected and we don't really know the history. So it could well be that the, there's an in, there's a family history here. So given the factor hemophilia A is a lot more common than hemophilia B, which is more common than Factor 11 deficiency. We're thinking this is probably hemophilia B, but we're gonna be looking for everything. It could be a type three, Von Willebrand. So we'll be looking for that as well. And when we do the testing, the factor eight is undetectable, but the factor 911 and 12 are normal and we've done a VW in there which is normal. So this will be consistent with hemophilia A or inherited factor eight deficiency. Now, there's a huge spectrum of hemophilia A S cos we've learned already that normal would be a factor level of 50% or 50 inter international units per deciliter plus. Um And we don't really find that people struggle that much with hemostasis until it gets the levels get very, very low. So we have a severity rating which puts hemophilia a patients into severe, moderate and mild. And if you have a factor level of 5% or more, then we think that you're gonna have a mild bleeding phenotype, you only need a little bit. But even those guys can sometimes get significantly and they may need support through procedures. They may need support through injuries. Rarely, they may get things get problems. But on the whole, they're not gonna have as severe problems as other, other people. And the key thing that people end up running problems with is spontaneous bleeds either into the head at birth after a traumatic birth or even just a normal birth, which can be quite traumatic or commonly, the big problem is into joints. So, hemarthrosis where blood gets into the joint makes it very big. So, and blood is very irritative and can lead to significant damage to joints to the point of severe disability within the first two decades of life. So a lot of hemophilia centers will spend a lot of time putting patients on to prophylaxis. So they'll be on regular factor replacement to cover day to day wear and tear. So they don't have bleeds in the first place. And if they do have bleeds being very aggressive in management and also involving physiotherapists and orthopedic people to manage that joint disease very, very well. So people can have long term ability. But historically, hemophilia patients who survived into adulthood, used to be quite severely disabled. But it with today's prevention strategies, prophylaxis strategies, we're trying to minimize that to the point where that is undetectable and when it's less than 1% that's where it goes down to the severe category. And those are people who have spontaneous bleeds quite commonly. And we will often get those onto something to stop it. In this case, this is consistent with severe with a major intracranial bleeds. And we need need to be very quick in managing this getting some factor factor replacement into this baby to and then some neurosurgical input to sort out the bleed and try and sort things from there. So this is a scary. It's also the case that got me into hematology in the first place because I used to be a pediatrician. My all my life case four, we've got 17 minutes. So we are on time case four. So in this case, we've got a seven year old presenting with gram negative sepsis. So this is quite a nasty sepsis that often lead to septic shock, cos gram negative bugs often lead to third spacing so difficult to maintain your BP. So quite often they need to go to um intensive care for ventilation. So intubation and ventilation. So a breathing machine and inotropic support. So being on presses to support the BP allow that heart to pump effectively to get uh blood round to the tissues. The platelet count is low. So we're thinking, oh, is there an issue with primary hemostasis here? But we've not heard about the bleeding history and that's the key thing here. Um is you always have to correlate the numbers with what's going on with the patient. So, is there bleeding? Is there bruising? It's the first question you're always gonna be asking. The blood film shows the occasional fragment. But the cl clotting screen is also shows a gross abnormality. And given the clinical picture here, we'll be thinking that there's something going on causing gross inflammation and activation of um the uh of coagulation to try and stop the insult. but it's dysfunctional here and happening in uncontrolled way. So in this circumstance, we'll be expecting that the lines will be, you know, when they've got arterial lines in or big um central lines in, there'll be probably oozing from the sites cos the platelet can't be low. All the clotting factors will be um vanished as well to other areas. There'll be a process of uncontrolled clotting, leaving no platelets or factor left over for normal control of hemostasis at other areas. Um and the D diers. So the product, the fibrin degradation products. So when the fibrin clot is formed, you'll have uncontrolled fibrinolysis as well. So you'll get degradation products and this D dimer is what you'll see in thrombosis. So they're, they're trying frantically to break down that clot, but it's not working very well. So you get D dimer very high. Um But it can also happen in, in this condition called D IC, which we talked about earlier. So this is a classic story for the, a very profoundly septic patient with gram negative sepsis, profoundly unwell. So, septic shock requiring lots of organ support. And they have this picture of thrombocytopenia, gross coagulopathy and raised products of fibrin degradation. There are again, the is th the International Society of Thrombosis and hemostasis has calculators to look at D IC and gives you ad IC score. So you can track progress looking at different parameters dynamically over time. So quite often a hematologist might ask you to look at that over time to see if things are improving. We might this will be churning through Vitamin K So we'll recommend some Vitamin K replacement, but we're gonna be quite cautious with clotting factors. Cos we know that the there's a high risk of thrombosis and we want to find that happy balance between the thrombotic potential and the coagulopathic potential. So, if they're showing a thrombotic phenotype, but they're not bleeding too badly, we we'd hold off things that would support things that support sort of product support. Cos f FP cryo things like that might make the thrombosis work. We'll be working very much in line with the clinical picture to guide things where if they're bleeding, we'll be saying, right, let's support the process. Let's give um you know, fibrinogen support. So give cryoprecipitate or fibr fibro and concentrate they're really struggling with, with the, with the deranged coagulopathy will be giving other things as well such as F FP sores and plasma to try and replace that factor. We're working quite hard to try and get on top of things depending on the clinical picture. And this is a process really. So it's a consumption coagulopathy. So there's uncontrolled coagulation, using up those platelets and clogging places leading to organ ischemia, microthrombosis or even grosser thrombosis versus bleeding at other sites because there's nothing left over. So with the case five more into the realms of adulthood here. So a 57 year old man, he's got deranged LFT S and a significant alcohol history. So we're thinking that he's got some sort of liver disease going on here. But most importantly, always take a bleeding history. He's got no history of bruising or bleeding, but we still do some blood that shows him to be mildly anemic with a macrocytosis, white cell counts. Ok? But the platelet counts are a little bit low and the PT is low so high and the A PT is high and the fibro is low. So it looks potentially, if you're looking at the in the wrong lens, you might be thinking right is this D IC, you know, the platelet counts low, you know, he's got some something's going on. But in the s in the consequence of sig of confirmed alcoholic liver disease or chronic liver disease, particularly when it's quite marked. And you've got a cirrhotic liver, then you might end up with a picture where the liver is not able to produce its factors but in hemostasis, we talked already that we have this natural balance between thrombotic prothrombotic factors and anticoagulant factors. You have natural anticoagulants. Um And so in, if you have a global depression of all those, you end up with something called rebalanced hemostasis where the platelets are low. But the von Willebrand factor is also a little bit off the coagulation factors and the anticoagulation factors are balanced fibrinolytic factors versus anti fibrotic factors are all depressed in balanced hemostasis. So even though the numbers which only measure one side of the equation are deranged. Sometimes even grossly deranged. When you look at the patient, they're not bruising or bleeding, they're in rebalanced hemostasis. And so increasingly we're evolving our mindset in liver disease to understand what is normal for that patient. Because if you chuck in loads of platelets, if you chuck in loads of F FP and tip the scales the wrong way, you might actually end up causing more harm than good, you might cause more issues with. Um so thrombosis, you might end up causing fluid overload, you might cause more harm than good. So, understanding that is, is really important and you're increasing cos it is a new concept. As doctors going out into the the field in the next few years, you'll find people who have historically manage these, these, these, these numbers rather than the patients in front of them um with very aggressive F FP cryo platelets and everything else to to manage procedures. But increasingly we understand that we don't need to do that. We may be causing more harm than good and there's increasing er, evidence and guidelines out there that say in these patients, particularly for low risk procedures, we should not be stepping in, we should not be doing that. We're going to be causing more harm than good case six. We've got an 89 year old who's been well established on Warfarin for a history of atrial fibrillation. So this is a condition where the heart is fibrillating and um well, occasionally cos it the, the, the heart chambers aren't moving, you'll get blood clots and it'll pump uh randomly and that blood clot will be thrown off and cause a stroke or something else. So you want to manage that and, and thin their blood to stop that happening. But in this circumstance, they presented with a, an acute kidney injury and Warfarin is largely excreted by the kidney. Um and you're worried a bit that, that may have accumulated and they've presented with bruising and bleeding. So you check their I nr their full blood count is normal, but their I nr is 11 and normally in patients, you, you're aiming for an I NR of 2 to 3, which is 2 to 3 times the pt of a normal person as it were. Um So we think that basically they've, they've been taking their warfarin, it's accumulated cos it's not being excreted and we could test their factor levels. So their factor 279 and 10 would be low. But we don't really need to. The history here is very suggestive. We would manage the, the warfarin toxicity or accumulation due to AK I. So this is very much targeted to the patient in front of you. You can give antidotes for warfarin. We've got lots of them, we can give Vitamin K which reverses all this. Um But if we give loads and loads of it, we'll be swamping the body and it'll take a long time to get warfarin. So we might go low and slow and give 1 to 2 mg and then reassess after 4 to 6 hours when it has a chance to, to bend and it takes that long to sort of disperse in the body and have an action and 2 mg would probably be enough to get this down. You might need another further dose to get it further down. But if you gave them 10 mg, you probably couldn't re warfarinise them for weeks and they'd need some sort of cover if they were high risk from, from their af however, if they're bleeding, you want to do something there on them. So we give something called PCC or prothrombin concentrate. So we, it's basically uh either a, a three or four factor concentrate geared towards these factors and can reverse um the, the bleeding phenotype within, you know, minutes. Um And So we will give that as either octaplex or beriplex depending on where you work. And we can give that as an emergency reversal if we need to. OK. Seven. So it's a 23 year old woman presenting with confusion, renal dysfunction. She's noted to be anemic with a very marked thrombocytopenia. And the blood film shows loads of fragments, but the clotting screen is plumb normal. So this is pre predominantly er AAA platelet issue. And this is actually an issue of TTP which we talked about earlier where you your Von Willebrand is normally forms multi. So it forms like little chains that go off and foot work their action and those are cleaved into the right length by this enzyme called Adam TS 13. You can get a deficiency of Adams TS 13 either because you're born with a deficiency called congenital or you have an antibody that destroys Adams Ts 13. So it's an acquired antibody mediated um Adams TS 13 deficiency where that doesn't happen. So these long MERS and you may remember that um the one would have, in fact, it binds to platelets so that platelets all bind to those very long ers and they cause these huge great things that go off and cause micro thrombi which cause renal dysfunction, brain clots um and they consume all those platelets and they can also cleave off all the and they also block off into the er micro FCA and the red cells going through, get shorn into pieces. So you end up with a hemolysis as well. And this is the thing that is life threatening within a day or two. Um, I think that was the last case. Right. Er, does anyone have any questions? So, I think we've got some in the chat. Um, can you see I can, so I can see doctor Ay, um, in those with severe renal impairment or if dox are contraindicated eeg due to a lupus anticoagulant who are at high breeding, er, bleeding risk on the basis of preliminary specific studies on could inhibitors of factor 11 have potentially replace warfarin. Ok. So that's a really interesting question. So you're basically saying, so we've got new agents coming out um which work in completely different ways. Um They haven't been explored in any sense for prevention of thrombosis. In fact, the latest preliminary things coming out from Pacific and the er, ancillary studies is actually that they have actually halted those studies cos they're not proving to be efficacious, they're having more thrombo thrombotic risk than anything else. Um So those aren't really coming through yet uh as a thing. Um We're always looking for new targets. Warfarin is a tricky drug. You have to monitor it, it can accumulate, but in s in end stage renal failure, it is currently the only thing we can use. Um we have are looking ever more at um when we can use half dose to act to reduce stroke in er people who have um severe renal impairment. But as it currently stands, the only data is around Warfarin, there is increasingly trying to use Apixaban trying to use Lemli Great Heparin with some anti 10 A levels to try and understand it. But we're not there yet. If you've got a four an indication for anticoagulation, the only thing really at this current moment in time is warfarin, we hold great hope for the future in terms of rebalancing agents in terms of other things we can use. But nothing is there yet. I hope to answer your question there. Second question. Um is uh can hypercalcemia? I think you're trying to say that in some cancers, contrary to high stage. Um yes, there's a huge amount going on in cancers that lead the procoagulant states. Um It's mostly to do with um localized effects. It can be to do to do with cytokine effects, which is probably the most of it where they lead to a, a hyper inflammatory state that leads to a procoagulant state. Cos that's part of uh child's trials and you can get lots of, er, cytokines and er, hyperviscosity symptoms as well. Er, if you can do that, but hypercalcemia when it's present can not help, but it wouldn't be the, the sole answer can forgive me. Read what? Wrong with her. And then we've got one from Rajat Roy um that you kind to clarify the difference between an anticoagulant and an antiplatelet. That's a really great question. I haven't really touched on this today. So an antiplatelet works on platelet aggregation or um platelet adhesion. So it works in primary hemostasis, whereas an anticoagulant will work on the secondary hemostasis. So it will work on the clotting cascade. Um in one of the ways we've described in this lecture actually, and um basically secondary hemostasis is more of a factor in venous thrombosis. Um So that's where you have a chance for the blood is flowing a little bit slower, you can get um sort of an easier time of things to form a clot. Um And so, if you have a venous thromboembolism, it's normally due to something happening in the secondary hemostasis pathway. And therefore, that's gonna be more efficacious. So, in DVTs, ps, um trying to reduce the viscosity of turbid blood in af that will reduce, that will help there. Whereas in arterial disease. So, peripheral vascular disease or in um where you're thinking peripheral vascular disease or um a stroke has occurred in the arterial tree, it's more likely that the the benefit will come from affecting primary hemostasis because blood is flowing under much more sheer strength and often that's more of the the difference. So, in stroke prevention in er vascular disease in arterial disease and antiplatelet is much more helpful. Whereas in venous disease. So venous thromboembolic disease, um a er anticoagulant is more helpful, does that answer your question, doctor or mister Mister Ryan. Don't know. Not sure how long it might come for that to come up on the messages but I'm sure he'll get back to you. Ok. Um, does anyone else have anything else that I left? I didn't thank you. Um, that's come up, er, does anyone else have any other questions or anything else that they've come across that they wanted to ask about? Cos cases are, er, the way that we will learn from time to time, er, or any other feedback that you would like to just, er, state and we'll put the link for the feedback in the chat as well. Yes. So if, um, there are no other questions, um, then I just wanted to thank you very much, Doctor Clark, I'm sure everyone, um, enjoyed it as much as I did. Um, and I'll post the link now in the, for the feedback so that, um,