S1E38 Bleeding & Coagulation Disorders

All right, so we're going to be only over bleeding and coagulation disorders, specifically hemophilia, A and B, foundolabran disease, factor five, Lyden, and protein, CNS deficiencies. Sometimes people have trouble with these. Just, you know, there's not really that much to know, but they can just kind of all get mixed together. And sometimes it's hard remembering which is what. And so I'm going to do my best to focus on the main things that you need to know and help you to just remember them for the exam and what you really need to know for these. So thank you as always for the really great comments. You guys are absolutely the best and I appreciate it so much. So thank you so much for that. If you haven't checked out, I have an Instagram page and a YouTube channel as well under Cran the Pants. Check those out. There's some other things that may help you for school. So let's go ahead and get started with our bleeding coagulation disorders. And let's start with the one that you'll probably hear the most about. So that's hemophilia, A. This is your most common type of hemophilia. Not your most common type of bleeding disorder, but your most common type of hemophilia. More common than hemophilia B. So it's the one you'll hear about more between hemophilia A and B, which are very similar between the two. I'll go over the few differences, but essentially clinically they're the same. Now this is an excellent recessive disorder. So as far as your vignette, this is 100% going to be a male in the vignette. It affects the X chromosome, meaning if a male gets it, males only have one X chromosome, they have the disorder. There's no avoiding it. Females on the other hand have two X chromosomes. So they still have an unaffected chromosome. So they're usually going to be carriers. The way that I used to remember this was, I used to remember chemo fill. Yeah. So the name, it has fill in it. So hemophilia has fill in it. Fill is a common male name. I always just just think of Dr. Phil and like his bald head. And as soon as I would see hemophilia, I would say, OK, I know this has to be a male. It would help me narrow it down. So it's little things like this that are going to help you in vignette. So you're going to have a question months from now. You'll see hemophilia and the answer choices. You remember a damn thing about hemophilia. But you'll remember Dr. Phil's bald head. I'm telling you, you will. And then you'll be like, oh, yes. So this is only seen in males. The patient in the vignette, maybe it's a girl. And then you're like, OK, I can eliminate hemophilia. It's not going to be hemophilia because this is a female. And I remember this is only seen in males. So is it possible with women to have the same presentation as a male? It's possible. It's very rare. It's only if they have an ex-chromosome loss or deletion way beyond the scope of what you need to know for the boards. Again, it's rare. They're not going to trick you like that. So as far as you need to know for the exam, this only happens in males. Look for a male in the vignette. And remember Dr. Phil, hemophilia. So only males for hemophilia. This is a deficiency in factor eight. I used to remember this because when you say the number eight, the first thing you say is A. So hemophilia A, A, T. You see what I'm saying? So you say A when you say eight. So hopefully that makes sense. That used to help me remember it. So deficiency in factor eight. So as far as the path, though, it's really straightforward. You have a deficiency in factor eight. Factor eight is part of the coagulation cascade, specifically the intrinsic pathway. And if you have low factor eight, you have disruption and decreased ability to form clots. Nothing really complicated there. Just remember factor eight. So all right, clinical manifestations. These patients are going to bleed. They're going to have GI tract bleed, urinary tract, eucosal membranes, intracranial bleeds, a bunch of different ones. But the only one that you need to know, the one that's most unique to hemophilia, that's again, what you need to do for these exams, focus on the things that are unique, is going to be hemarthrosis. So that's bleeding into a joint space. It's the most common sight for bleeding in your ambulatory patients with hemophilia. And it's, represents close to 80% of the hemorrhages you'll see in hemophilia. So really prominent in this disorder. So as far as clinical manifestations know this one, how are you going to see it on a vignette, though, how are they going to give this to you? So it's going to be a patient. Obviously, it's going to be a male. It's often going to be a young boy. And they'll say he had a minor accident. He bumped his knee at the playground. Now he has this grossly swollen knee or elbow, wherever they bumped it, basically swelling out of proportion to the injury. They also may mention that he's had this persistently painful joints. He limps on his leg, always complaining of his knees hurting his ankles, et cetera. So look for that hemarthrosis. They're going to give it to you in the vignette, because that's the most common presentation. Now diagnosis, this is important. So your PT, your pro-thrum, and it's going to be normal. Your PT, your partial thromboplastin time, is going to be prolonged. So remember PT and PT are your clotting time. The measure how long it takes to form a clot. But why is your PT prolonged and your PT just normal? Helps to understand these things to remember them for the exam. So let's go over what PT and PT measures. So PT measures the extrinsic and the common coagulation pathways. So PT is going to measure 1, 2, 5, and 10, as well as 7. So 7 is going to be the extrinsic pathway. 1, 2, 5, and 10 is going to be the common coagulation pathways. Now PT, partial thromboplastin time, the one that's going to be prolonged, again, measures your common pathway. So that's going to be 1, 2, 5, and 10. But it measures the intrinsic pathway as well. And what's included in the intrinsic pathway? That's factors 8, 9, 11, and 12. What did I say? They're 8 and 9. So that's specifically what's decreased in hemophilia A is factor 8. And then hemophilia B is factor 9. So that's why you see a PT that's going to be prolonged. That's going to be abnormal in hemophilia A and B. Because your PT measures your intrinsic pathway, which includes factors 8, 9, 11, and 12, where PT does not. It only measures the extrinsic, which is going to be factor 7. That's why your PT is going to be abnormal or prolonged in hemophilia A and B. Just the heads up, it's possible in a patient with mild hemophilia to have a normal PT. So I always want to do confirmatory testing with factor 8 assay to see if that's decreased or have since the factor 8. So remember your PT is going to be abnormal. And then you also check for your factor 8 assay to see if that's decreased or absent. Now treatment-- so there's two things you need to know. Factor 8 infusion-- so they're deficient in factor 8. You give them factor 8. It can be used for prophylaxis. It can be used during an acute bleed. It's really your best treatment, but it's not your first treatment for hemophilia A. So in hemophilia A, you have another treatment option. And that's with Desmo Pressing, also known as DDAVP. So Desmo Press in DDAVP is really going to be your first line in mild cases of hemophilia A. So if you have a little boy who came in a bump Disney, you realize he has hemophilia A. That's where you'll start with. You're not going to give them these IV factor 8 infusions. So you start with Desmo Pressing. So why do you give them Desmo Pressing? What does DDAVP do? So it stimulates release of something known as Von Willibrand factor. And why do we care about releasing Von Willibrand factor? Well, Von Willibrand factor is actually partners with factor 8. It binds to and stabilizes and decreases the degradation of factor 8. So we have more Von Willibrand factor with DDAVP. We have an increased stability of factor 8. So it stays around longer, which is obviously important here. So patients with mild hemophilia A, you have the additional option of DDAVP. Keep in mind, this is not going to be an option for hemophilia B. Because hemophilia B involves factor 9 deficiency, which we'll go over next. Von Willibrand factor has nothing to do with factor 9. He's only buddies with factor 8. So you only use this in hemophilia A. What do you need to know for hemophilia A? You need to know it's a factor 8 deficiency. You remember factor A to deficiency. You need to know it's going to be a male patient. This is excellent recessive. So hemophil, Dr. Filia, PT is going to be increased, but not your PT. Then you need to know not only can you treat them with factor 8, but you can also treat them with DDAVP Desmo Pressing, which is generally going to be your first line treatment for those mild patients. Hemophilia B. I'm going to run through this one fairly quickly because hemophilia B is almost identical to hemophilia A outside of a couple of differences, which I'll go over. The first difference is obviously this is the deficiency in factor 9, not factor 8 like we did in hemophilia A. I used to remember that because I would just remember benign. Like the tumor is benign B9, and that helped me remember hemophilia B. Maybe that does not help you at all, but it always helped me. I never forgot it. So hemophilia B is a factor 9 deficiency benign. The tumor is benign. Excellent recessive again. Remember, Dr. Phil, this is only going to be seen in males. Females are going to be carriers, but males will be the ones that are going to be symptomatic, most cases. Clinical manifestations. Again, they're going to bleed GI, track urinary tract, blah, blah, blah, mecocell membranes. But you'll remember hemarthrosis because that's going to be the most common. So you're going to have that hemorrhage into a joint. Diagnosis, same thing here. PT is going to be normal as well as I think over this in hemophilia A, but as well as your platelets, your fibroindrogen, all that's going to be normal. It's just your PTT that's going to be prolonged. Same reason I just went over because PTT measures your intrinsic, which has factors 8 and 9 included. If you ever forget which measures which, like PT, you forget the measures extrinsic and PTT measures intrinsic, this is what I came up with. So you have PT and PTT. So in PTT, the T and the T are side by side. It almost looks like they're holding hands. And that's because in PTT, T and T are in love. AKA intrinsic pathway. PT measures the intrinsic pathway. Because T and T are right next to each other. Like the top of the T's look like they're holding hands. They're in love. Remember, PT measures the intrinsic pathway pathway. And then PT, you don't see that second T there anymore. What happened? They broke up. They're X. is, or X is PT measures the extrinsic pathway. T's gone, he's out of the picture, he or she's out of the picture. They're no longer together, they're X's. So PT measures extrinsic, PTT, they're in love, measures the intrinsic pathway. Hemophilia B is going to measure the factor, or it's going to be a decrease in factor 9. So we also do a factor 9 assay. So that's going to be decreased or absent. And treatment, really the key to treatment compared to hemophilia A is only that DDAVP does more press in place, no role here. Remember what I said before, does more press releases Van Mullerbrand factor, Van Mullerbrand factor, Van Mullerbrand soon stabilizes factor 8. That's not a problem in hemophilia B. We only worry about factor 9. So DDAVP has no role in hemophilia B, only hemophilia A. So really the main treatment option for hemophilia B is going to be factor 9 infusion. So again, it can be used for prophylaxis, during an acupelate. It's really your best treatment option for hemophilia B. So what's different compared to hemophilia A as we went through it? Really there's only two things. First, this is a factor 9 deficiency rather than factor 8. And then second, DDAVP is not going to be used, only factor 9 infusions. Otherwise, everything else is pretty much identical. So what you need to know for hemophilia B, remember it's a factor 9 deficiency B9, tumor's benign. It's going to be seen in a male patient, Dr. Phil hemophilia. PTT is going to be increased, but not your PT. And then you use factor 9 for treatment, but no DDAVP. DDAVP is not for me in the hemophilia B. All right, so Von Willough brand disease is our next one we'll be talking about. So this is a decrease in the quality or the quantity of something known as Von Willough brand factor. If you remember, I went over this in TTP. In TTP, we had an increase of Von Willough brand factor. But in this, we have a decrease. So in TTP, we had a clotting problem. And Von Willough brand disease we're going to have a bleeding problem. That's because Von Willough brand factor or sticky willy as I like to call him, his job is to act like glue for platelets, kind of like sticky paper for flies, but in this case for platelets. So if you have an injury to a blood vessel, you have an opening in the vessel. The body sends willy to come in, snatch up a bunch of platelets to form this platelet plug. But in Von Willough brand disease, there's not enough of willy or willy's just not doing his job. So the quality of willy is decreasing or the quantity. And that's the problem in Von Willough brand disease. You have this ineffective platelet adhesion due to a problem with willy, which leads to bleeding. Another thing you need to know for Von Willough brand disease is that it is the most common bleeding disorder that affects up to 1% of the US population. So it's really common, actually. There's a few different types of Von Willough brand factor. There's inherited, there's acquired, inherited. There's like three different subtypes. Don't worry about that at all. It's insane to memorize all of them. And it's a waste of time. The only one that I want you to remember is type one inherited. That's your most common type. About 75% of the cases are type one inherited. Therefore, that's the one you need to know because that's the one that will likely quiz you on. So, in Von Willough brand disease, remember type ones are most common. About 75% of patients is an autosomal dominant disorder. Now, clinical manifestations, there's a couple of things. You're gonna have mucus, ocutaneous bleeding, and you're gonna have excessive bruising. That's the ones you should know. So, there's really just those couple of things. So, a mucus ocutaneous bleeding, like epistasis, bleeding following dental procedures. And then they're also more susceptible to bruising. So, there's other clinical manifestations, of course, but those are the ones you should focus on. They're the more common ones to look out for in the vignette. So, remember, look for a nose bleed. They may mention they had a dental cleaning and they had all this excessive bleeding. They may say that they're always bruising or they bruise very easily. That's what you should look out for there. Now, diagnosis. This is gonna sound similar. So, PT is going to be normal. Your PT is going to be prolonged. So, that's exactly the same as hemophilia. So, why? So, why is your PT prolonged? You told me, I told you before, PT measures factors in the intrinsic pathway, like factors eight and nine, but this is a Von Willow-brand factor problem, not an intrinsic pathway problem. So, why is PT prolonged? Well, it actually is an intrinsic pathway problem. If you remember what I told you about before with the treatment. So, what we talked about before, how is Willey's relationship with factor eight? Remember, Von Willow-brand factor essentially protects factor eight. It's like his big brother helps him to stick around longer. While in Von Willow-brand disease, there's not enough of Willey around or he's not functioning the way he should. So, we're gonna have this increased factor eight degradation and less of factor eight overall. So, a PT, which measures the intrinsic pathway, including factor eight, that's why PT is gonna be prolonged in Von Willow-brand disease because we're having that breakdown of factor eight. And that's why we have the same problem that we had in hemophilia. So, Von Willow-brand disease in general, another thing, it's gonna be worse with aspirin use and you may hear that brought up a lot. So, your PT and your bleeding time will also be prolonged with aspirin use. It'll be worse when these patients take aspirin. It's pretty common sense though, because as I went over before, Von Willow-brand disease is a problem with platelet adhesion. So, aspirin's an anti-platelet. So, it makes sense this disease is gonna be worse. Just remember that 'cause they may bring that up. That all of a sudden they took aspirin and all of a sudden their symptoms are worse, their bleeding's worse, et cetera. Another thing to look for in the diagnosis, there's Von Willow-brand factor antigen and Von Willow-brand factor activity. Don't go too crazy with this, but just know they're gonna be decreased or no platelet aggregation. There's a variety of screening tests. You don't need to know all of them. Just know if they mentioned of Von Willow-brand factor antigen in its decrease. Most likely gonna be Von Willow-brand disease. One thing that I'll mention because it's kinda unique and interesting that maybe we'll come up, maybe it won't. But, Von Willow-brand factor activity test, the way that you measure this, and this is, I find it interesting, so maybe it'll help you remember it, is with something called Ristocetan. So, Ristocetan, specifically Ristocetan co-factor, it was an antibiotic we used years ago until it was discovered it caused platelet agglutination. So, when you add Ristocetan to plasma with normal Von Willow-brand factor, causes all of the platelets to clump together, and you can visualize this coagulation. But when you do the same thing, you add that Ristocetan to plasma and a patient that has Von Willow-brand disease. This patient will not have that platelet aggregation. So, that's what you're looking for. You actually use this antibiotic that we don't use anymore because of that specific reason, to see if this patient has a decreased or non-functioning platelet aggregation in patients that have Von Willow-brand disease. So, that's why you use that, and that's how you check the activity of Von Willow-brand factor. Now, treatment is going to be mainly with DDAVP, Desmo Pressing, for your mild patients. So, Desmo Pressing, as we went over in Hemophilia A, I know this is getting repetitive, causes the release of endogenous Von Willow-brand factor, and this is going to be the one you'll use most frequently. And the answer likely on the vignette is going to be using DDAVP for treatment of Von Willow-brand disease. You may have also, you have the other options of Von Willow-brand factor concentrates. So, this is a combination of Von Willow-brand factor and factor eight, and it's administered intravenously. So, you're gonna use this in type three, or severe cases of type one and type two. So, this makes sense because DDAVP, you can use in mild patients or in type one. Now, type three, I don't wanna go too much into the different types, but just so you kind of understand why we use this instead of DDAVP. So, type three, Von Willow-brand disease, you actually have almost no Von Willow-brand factor in the body. The body's almost completely depleted. And then if you have type one and type two, severe cases, again, you barely have any DDAV, or you barely have any Von Willow-brand factor in the body. What does DDAVP do? Well, it encourages the release of endogenous Von Willow-brand factor. But if you have no Von Willow-brand factor in the body, what's DDAVP, what's Desmo Pressing gonna do? Can't do anything if you don't have enough endogenous Von Willow-brand factor, and that's why in type three, which has like no Von Willow-brand factor, or in type one and type two, severe enough cases, you don't have enough loading around, so DDAVP isn't gonna do much. So, that's why DDAVP, Desmo Pressing, while it's very useful in mild cases, you can't use it in type one and type two, severe cases, or type three, where there's really like little to no endogenous Von Willow-brand factor. Hopefully, I made that clear enough. Okay, so what do you need to know for Von Willow-brand disease? Need to know that this is gonna be a decrease in the quality, or the quality of Von Willow-brand factor. You need to know that these patients are generally gonna have mucus, mutaneous bleeding, and easy bruising, and then you need to know as far as treatment, DDAVP is the main thing to focus on, but be aware in certain specific populations, like I went over, Von Willow-brand factor concentrates is going to be another option. All right, let's move on to factor five, Liden. This is a single point mutation in factor five, leading to a hypercoagulable state. Factor five, it's a part of the clotting cascade, helps form clots by amplifying the production of thrombin, thrombin is an enzyme that converts fiber inage into fiber into form our fiber in clots. Anyways, factor five, he helps us form clots. Thank you for that factor five. That is very helpful, but the problem with factor five is he doesn't only have a stop button, he just keeps going and going and going and helping to make all of these clots. So someone needs to be around to tell him when to slow down. So then we have a protein that comes from the liver, it's called protein C. Protein C goes up to factor five, tells him when he's done enough, and says protein C to factor five says slow down, you've made enough clots, we're good. So that keeps factor five under control. so we don't have clots all over the place. On factor five, widen. And due to this point mutation that factor five now has, he no longer can be cleaved or inactivated by protein C. So he does whatever he wants. So think about the point mutation in factor five as ear moths. He can't hear protein C telling him to stop anymore. So he just keeps going and going and making more and more clots. So that was a mouthful. But nice and simple factor five makes clots non stops through the coagulation cascade until protein C says, OK, that's enough stop factor five. But in factor five, lighten factor five is no longer listening to protein C. He's got his ear moths on. And that leads to this hyperquagulable state and a bunch of clots. So it is the most common cause of inheritable hyperquagulable state, specifically in Caucasian patients. To remember that, this is kind of silly, but it always helped me remember. So factor five lighten, which is FFL factor five lighten, not the V like Roman numeral, factor five lighten FFL to me stood for frequently forming lumps. That's how I used to remember like the clots frequently forming lumps. Then help me remember is the most common cause of inherited hyperquagulable states. Remember factor five lighten if you see this patient with clots, that's going to be your most common cause and most likely be the answer. So if they could if they ask you the most common inherited cause of hyperquagulability, it's factor five. Remember that's going to be Von Willow brand disease. Remember factor five lighten frequently forming lumps. Hopefully that makes sense or helps you clinical manifestations. Well, they're going to have venous thromboembolism. So this is going to be the main clinical manifestation. We're going to that's what they're going to give you on the vignette in real life. Only around five to 10% of patients factor five actually go on to develop venous thromboembolism. But anyways, that's what you're going to see on the vignette. So look for your DVTs, your PEs, your clots. Another thing an interesting thing is that these patients often have miscarriages. So there's a data showing that factor five lighting can lead to unexplained recurrent late pregnancy loss. It's assumed that this is due to the thromboysis of the placental vessels. It's another thing I remember them liking to mention in the vignettes is a history of multiple spontaneous miscarriages. So look for that two with factor five lighten look for your clots. Look for your for them to mention these miscarriages diagnosis genetic testing is going to be a big one. So you have a patient that comes in you suspect factor five lighten they have this recurrent venous thromboembolism they have a family history of recurrent venous thromboembolism. You're going to look for that point mutation we discussed before with genetic testing. Nothing really specific to hear to know for the exam your PT and your PT are usually going to be normal. You can also do a functional assay to test for protein C resistance. And the protein C resistance the functional activated protein C resistance as it's called. You normally do this first and if it's positive then you move on to your genetic testing to confirm just because genetic testing is more expensive. So a lot of times you'll start with your functional activated protein C resistance test. If that's positive then you move on to your genetic testing look for that point mutation. Now treatment it's pretty easy. It's really just anti coagulation. So whether it's done prophylactically prior to surgeries or indefinitely depends on the risk factor of the patient. So what do you need to know? Need to know this is a mutated factor five out of control leading to a hyperquagulable state. Factor five's while and out protein C can't do anything to stop them. Remember it's the most common inherited cause of hyperquagulability. Remember frequently forming lumps. Look for your venous thromboembolism and your history of miscarriages and then treatment basically with anti coagulants. Pretty simple. Alright, let's move on to our last one protein C and S deficiency. There's not a lot to know here. You're going to have a decrease in protein C or protein S which leads to a hyperquagulable state. So the patho don't dive too deep into this because it can become pretty complicated but protein C and S they both come from the liver. They combine with something known as thrombin and thrombomodulin. They cleave and inactivate factor five as we discussed previously. But also protein C also cleaves or inactivates factor eight and the end result is this prevents excess coagulation or fiber information during secondary hemostasis. So just to make it super simple what I just remember protein S and C stand for stop clots. Protein S and protein C stop clots. That's what they do. They decrease clots by inactivating factors five and eight. So divisions you need or one of these can lead to a hyperquagulable state because factor five and eight, how long are being shut down or cleaved. Clinical manifestations pretty similar to factor five light and you're going to have your venous thromboembolism. They're more prone to DBTs, PEs. One thing that's a little bit more unique about this it's not exclusive to protein C and S deficiency but it's more common. It's something known as warfarin induced skin necrosis. So patients starts on warfarin in the first few days they may develop skin necrosis. Why does this happen? Well, it's due to protein C deficiency but let's actually explain that. You want to fast forward about 30 seconds you'll not have to hear this but I think it's important to kind of understand. So there's a few different mechanisms at play here. One is just how fast warfare and kicks in but one of the main causes is actually from a protein C deficiency. So let's explain why that happens. So patients taking warfarin when they're first started in the medication or if there's a temporary interruption in therapy and they have to restart back on warfarin they actually should be bridged with heparin or another short acting anti-guagulant temporarily for the first few days. Not in all patients but usually are high risk patients you're going to do this in and the reason you bridge with heparin or one of those agents is because when you first start warfarin you actually get this transient hyperguagulable state. So within the first few days you can potentially start forming all of these clots if you don't bridge with heparin. So you can actually start warfarin to stop clots and in the first few days you can cause a bunch of clots. So what happens is warfarin works by in activating your vitamin K dependent clotting factors. So basically all of the clotting factors coming from the liver warfarin shuts down. So that's factors 27910 but it also remember what else comes from the liver is protein C and S. So they're also shut down. When all of these factors are shut down at the same time that's good we don't have any issues but the problem is they all have different half lives. So protein C has a really short half life only a few hours. So within a few hours protein C is actually shut down. It's not coming back due to the warfarin but your other factors they have longer half life. So some of your other coagulation factors actually have half life of two to five days. So it'll be a few days before these are actually shut down. And this is when you have this transient, pro-thrombic state due to your natural anticoagulants like protein C disappearing early on and some of your other clotting factors with longer half life still hanging around for a couple more days. So this leads to clots and ischemia and infarct and that warfarin induced skin across as we talked about due to the protein C deficiency. So it's the absence of protein C altogether that causes this problem and it's why we bridge warfarin with heparin or another short acting agent for the first few days in our high risk patients to prevent this from happening. All right. So diagnosis you do a protein C and S. So there's a variety of assay methods that can measure protein, CNS activity or levels. The diagnosis of protein C deficiency is established by just documenting a low protein C or S level. Genetic testing is not often used. It's not really widely available like we saw in factor five items. So really just doing that protein, CNS assay treatment is again is going to be anticoagulation like anyone else who develops a clot, you're going to use anticoagulation. It's appropriate for individuals with protein C deficiency normally who develop a thrombo and baleic event. You can also use protein C concentrate. It's often given prophylactically prior to surgery or in pregnant patients around the time of delivery. What you need to know for protein C and S deficiency, you need to know this is a protein C and S decrease level, which leads to hyperquagulable state. Remember protein S and C have the job of stopping clots. Remember look for your venous thromboembolism. Also your warfarin induced skin necrosis, which really complicated patho that explained and then remember as far as treatment you're going to use anticoagulation and then protein C concentrate. All right, so let's move on to five questions and we will wrap this up. All right, so question one, seven year old boy presents to the office today with significant swelling over his right knee. Whether states they were at the playground and he bumped his knee on the slide as he was coming down, she states he's always bruised very easily and often complains of joint pain. Patients studies show a prolonged PTT and plasma factor eight assay show decreased levels of factor eight. What would be the first line pharmacologic agent to administer in this patient? So that is going to be Desmopressin also known as DDAVP. So this patient has a clear presentation of hemophilia A, male gender, remember hemophilia, excellent recessive, remember hemarthrosis, which is the most common manifestation in your ambulatory patients with hemophilia, patient at a prolonged PTT, decreased factor eight. So we know it's hemophilia A and how do we treat mild cases of hemophilia A like this boy obviously had that's going to be with DDAVP which increases the release of endogenous Von Willoughbrand factor. That stabilizes factor eight in the body. Question two, what is the most common inherited bleeding disorder? That is going to be Von Willoughbrand disease seen in up to one percent of the population. Question three, 39 year old female presents to the ER with lower leg pain and swelling. A Doppler of the lower extremities performed to reveals a DVT. She admits this is her third DVT in the last few years. She also has a history of several miscarriages and admits her mother had similar problems with blood clots. Genetic testing in this patient would likely reveal a mutation in which clotting factor. So that's going to be factor five. So first, factor five lied in is your most common cause of inherited hyper-quagulable states. So always be thinking factor five before anything else, protein, c-rest deficiency. So especially in your Caucasian patients, which factor five lied in the scene much more commonly in. So patient has multiple DVTs. We have a family history of DVTs plus miscarriages, which we know is another potential problem. In factor five, lie in. So most likely cause of this problem is by this patient having a mutation in factor five leading to the resistance to it being broken down by protein, c. Question four, hemophilia, b is a deficiency in which clotting factor. So that is going to be factor nine. Remember that tumor is benign b nine. All right, question five, a 52 year old female who was recently started on warfare and for DVT prophylaxis begins to develop necrotic lesions on her legs and feet deficiency in which vitamin K dependent plasma protein likely led to this presentation. That's going to be protein C. So this patient has warfare and induced skinicosis. So remember with warfare and reason we bridge with heparin and low molecular weight heparin in our high risk patients is that transient pro-theromic state where warfare and initially where the protein CNS gets shut down and our natural anticoagulance and then the other factors takes a few days to get shut down. So we have that deficiency in factor or in protein C which leads to this pro-theromic state. So that is it. I hope that was helpful. Thank you so much for listening. Please let me know if it's helping you or if there's any suggestions you guys have for topics coming up or anything else really. So thank you so much as always and good luck on your pants, your panorier ERs and good luck in PA school.