all right so we're going to be going over bleeding and coagulation disorders going to include hemophilia a hemophilia b von willebrand disease factor 5 lyden and protein c and s deficiency sometimes these can be a little bit intimidating and i remember in pa school i always felt like there was a lot to know with these but really there's not and i kind of broke it down to just the basics you need to know but it's really just understanding the path on everything else is pretty simple before we start as always i wanted to thank you so much for the really nice comments the new subscriptions i just really appreciate it and i'm going to thank you every single time on every video so hopefully that doesn't get too annoying but thank you so much again for that let's go ahead and get started with bleeding and coagulation disorders and let's start with the one you'll probably hear the most about and that's hemophilia a so hemophilia a is your most common type of hemophilia much more common than hemophilia b it's not your most common bleeding disorder but it's your most common of the hemophilia so it's an x-linked recessive disorder this is really important because as far as your vignette this is 100 percent going to be a male it affects the x chromosome meaning that if a male gets it male is only having one x chromosome they have the disorder there's no avoiding it females on the other hand with 2x chromosomes still have one unaffected chromosome so they're usually going to be carriers um you do need to know this because it's going to help you in the vignettes the way that i used to remember this was i used to just remember that hemophilia has the word the name fill in it which is a pretty common male name and i always used to just think of dr phil so as soon as i would see hemophilia i think a fill and i think of dr phil and like oh yeah this should be in a male patient and it's little things like this that are going to help you on vignettes you're going to have a question months from now you're going to see him affiliate in the answer choices you're not going to remember a damn thing about hemophilia but you're going to remember dr phil's bald head and you're going to be like oh yeah this can really only be seen in males patient is vignette is a girl so there's one answer choice i can eliminate fyi it's possible for a female to have the disease and have a presentation like a male it's possible in in females with um and women with x chromosome loss or deletions way beyond the scope of what you need to know for the boards they're not going to ask you that they're not going to give it to you that way so as far as the boards are concerned and as far as what you need to know for the exam this only happens in males so look for a male when you see hemophilia think of dr phil remember this is only going to be seen in males now ex hemophilia a is a deficiency in factor eight so the first thing when you say the number eight you say the letter a so when you say eight you say a so you see what i'm saying that's how i used to remember hemophilia a was a deficiency in factor eight because as soon as i say hemophilia a i'd remember oh yeah eight so hopefully you get what i'm saying there so okay so it's um so as far as the patho it's straightforward you have a deficiency in factor eight factor rates part of the coagulation cascade specifically in the intrinsic pathway and when you have low factor eight you have a disruption and decrease ability to form clots there's nothing really complicated here just remember it's factor eight that you're deficient in in hemophilia a as far as clinical manifestations patients are going to bleed gi tract urinary tract mucosal membranes intracranial bleed but the one that you need to know the one that's going to be most unique to hemophilia that's what you need to start doing on these exams focus on what's unique don't learn all the things that are going to be the same for all of them you need to learn what's going to differentiate it and for hemophilia that's going to be hemorrhoids which is bleeding into a joint space it's the most common site for bleeding in your ambulatory patients with hemophilia and represents close to 80 percent of the hemorrhages you'll see in hemophilia so as far as clinical manifestations know this one how are you going to see it on a vignette how are they going to present this it's usually going to be a patient normally a young boy minor accident maybe they bump their knee on the playground now they have this grossly swollen knee wherever they bumped it they're gonna have swelling out of proportion of the injury they may also say that the kid has persistently painful joints always complaining of his knees hurting her ankle something like that indicating the heme arthrosis so look out for that in the vignette now moving on to diagnosis a couple things you need to know here first thing is your pt your prothrombin is going to be normal your ptt is going to be prolonged that's your partial thromboplastin time so remember your pt and your ptt are your clotting time they measure how long it takes to form a clot so why is your ptt prolonged but your pt is normal so let's go over that and kind of explain it and to understand it we have to know what pt measures and what ptt measures so pt measures the extrinsic and common coagulation pathways so that's going to be factors 1 2 5 and 10 and then specifically for the extrinsic part that's going to be factor seven so factor uh so pt measures these factors here one two five seven and ten and then ptt is gonna is gonna measure the intrinsic and common coagulation pathway so again we have the same thing one two five and ten they both measure that common coagulation pathway but the intrinsic part in ptt is what you need to know here that's going to be factors 8 9 11 and 12. what did i say 8 9 11 and 12. that's why your ptt is going to be prolonged because it's measuring the intrinsic pathway which includes factor 8 which is going to be what's abnormal hemophilia a and then factor 9 which is going to be abnormal and hemophilia b and that's why you'll also see a prolonged ptt and hemophilia b so that's why only your ptt is usually going to be prolonged because ptt measures the intrinsic pathway as well which includes those factors eight and nine so remember that's why you're going to see that abnormal lab finding now you're also going to do a factor eight assay that can be decreased or absent because of the you know deficiency in factor eight and that's important because in a patient with mild hemophilia it's actually pos it's possible that they have a normal ptt so you also want to do your factor eight assay to see if it's decreased or absent as far as treatment there's a couple things that you need to know here first you can do factor eight infusions they're deficient in factor eight so you give them factor eight it can be used for prophylaxis it can be used during an acute lead it's really your best treatment for hemophilia a but it's not usually going to be your first line so only in hemophilia a do you have another option and that's with something known as desmopressin also known as ddavp so ddavp is really going to be your first line in mild cases of hemophilia a so what does ddavp do so ddavp or desmopressin it stimulates release of von willebrand factor and why do we want von willebrand factor well von willebrand factor is actually partners with factor eight binds to and stabilizes decreases the degradation of factor eight so when we have more of von willebrand factor we have an increased stability factor eight so factor eight stays around longer which is obviously what we want in this disease so patients with mild hemophilia a you have the additional option of ddavp keep in mind i'll go over this again when we go into hemophilia b but this is not an option for hemophilia b because hemophilia b involves factor 9 deficiency von willebrand factor has nothing to do with factor 9 he's only buddies with factor 8. so remember that ddavp only an option hemophilia a so what do you need to know for hemophilia a you need to remember that this is going to be a factor eight deficiency remember hemophilia a8 factor eight deficiency you remember this is going to be a male patient remember dr phil x-linked recessive remember your ptt is going to be increased because of what it measures and then remember you can use factor eight and also davp specifically remember that one because that's unique for treatment all right let's move on to hemophilia b i'm gonna run through this one fairly quickly because hemophilia b is almost identical to hemophilia a outside of two differences that i'll go over but everything else is pretty much the same and clinically they present identic they're identical so let's go through this real quick remember x-linked recessive disorder there he is dr phil don't forget that you're gonna see a male in the um and the vignette this is a deficiency in factor nine not factor eight way that i used to remember that i just used to remember hemophilia b factor nine deficiency b9 benign like the tumor is benign i just used to remember benign and that used to just help me remember hemophilia b so maybe that works for you maybe it doesn't but b9 the tumor is benign hemophilia b um clinical manifestations this is going to be the same here remember they're going to bleed but remember that hemorrhoisis and 80 of the patients diagnosis identical pt is going to be normal ptt is going to be prolonged because remember it measures the um intrinsic pathway which includes those factors 8 9 11 and 12 so that 9 that factor 9 is included in ptt the way that i used to remember which measured what because sometimes you'll need to know does ptt measure intrinsic does pt measure extrinsic and you can't remember this is the way that i used to remember it so ptt you can see the two t's up top it's almost like the tops of the t's they're like holding hands and that's because t and t are in love so ptt they're in love and that's because ptt measures the intrinsic pathway and then pt t is no longer in the picture he's gone he's out of the picture you can see him down there crying and that's because t and t are broken up their x is and that's because pt measures the extrinsic pathway so that's just a little trick that i came up with if you ever forget which is which and you're like i can't remember what pt measures is extrinsic intrinsic remember is t still in love or are they x's are they broken up and that's how you can remember intrinsic and extrinsic pathway all right so then also remember in diagnosis you can check your factor 9 assay to see if it's decreased or absent and then treatment so treatment you're going to give them factor 9 infusions can be used for prophylaxis during acupully just like we did in hemophilia a but then the key here is you're not going to use ddavp remember ddavp only helps out with factor eight but hemophilia b is a problem with factor nine so no use of ddavp and that's key here so really the only two differences are going to be in hemophilia a is that this is a factor 9 deficiency rather than factor 8 remember b9 and that you're not going to use ddavp otherwise they're pretty much the same so what do you need to know factor 9 deficiency b9 male patient remember dr phil ptt is going to be increased your ptt your pt will be normal and then remember factor 9 for treatment but no use of ddavp all right let's move on to von willebrand disease so von willebrand disease is a decrease in the quality or the quantity of von willebrand factor which is going to lead to bleeding this is if you listen to my um thrombocytopenia lecture um we went over ttp which was actually a decrease or i'm sorry an increase in von willow brand factor which actually caused clotting well this is the opposite this is a von willow brand disease we have a decrease in the quality or quantity of von willebrand factor and that's why we have bleeding so lesser von willebrand factor so what does von willebrand factor do well sticky willy as i like to call him his job is to act like glue for platelets so kind of like sticky paper for flies but in this case platelets so you have an injury to a blood vessel they have an opening body sends willy out to snatch up stick to platelets to form a platelet plug to keep that hole in the ear having the vessel closed up but in von willebrand disease there's not enough of willie or willie's just not doing his job the way he should and that's the problem in von willebrand disease you have this ineffective platelet adhesion due to a problem with willy leading to bleeding so little diagram i made here in microsoft paint so it's terrible but it gives you the idea so this is your vessel here you had a little cut you had a little opening in the vessel so what do we do these little black sticks here that's your von willebrand factor so the body sends out a call for von willebrand factor it's obviously a little bit more complicated than this this gives you the idea and then what willow brand factor does is you have all your platelets here he just sticks to all the platelets so eventually you have enough of the platelets stuck here and you form a nice platelet plug which closes up and that's part of your primary hemostasis to stop the bleed quickly so that's the idea of von willebrand um factor and the problem we have in von willebrand diseases we don't have enough of these so we have bleeding okay so von willebrand disease this is important it's the most common inherited bleeding disorder one up to one percent of the population actually has von willow brand disease which is crazy um so the most common inherited bleeding disorder remember that if they ask you that now there's a few different types there's actually a lot of different types there's inherited there's a acquired inherited there's actually i think three different subtypes it's crazy to remember all of those i would never expect you or tell you to do that the only one i would tell you to remember is going to be type one and that's because that's your most common so type 1 inherited is going to be your most common type of von willebrand disease about 75 percent of patients so that's the only type i would really um commit to memory now clinical manifestations you're going to have a couple things you're going to have muco cutaneous bleeding and you're going to have excessive bleeding so there's other things that can go on with von willebrand disease but those are the only two that i would remember so much cutaneous bleeding like epistasis uh bleeding following dental procedures and then they're also more susceptible to bruising so those are the ones that i would focus on for your clinical manifestations as far as diagnosis this is going to sound very similar you're going to have a normal pt but your ptt is going to be prolonged same as hemophilia so you might be thinking why is my ptt prolonged you just told me that ptt measures factors in the intrinsic pathway like factors eight and nine but this is a problem with von willebrand factor not an intrinsic pathway problem but actually it is and that's because what we talked about before when we were going over what ddavp does desmopressin so willie his relationship with factor eight remember von willebrand factor essentially protects factor eight like his big brother helps him to stick around longer so when von willebrand disease there's not not as much of willy or he's not functioning the way you should and this leads to increased factor rate degradation and less factor eight overall and what is ptt measure factor eight as well as some other factors and that's why you're going to see that your ptt could potentially be prolonged involved willow brand disease because von willebrand disease is no longer protecting factor eight so that's why you're going to see it another thing that you may see mentioned i don't think it's important to really memorize this because it's common sense but a lot of times they'll mention that the patient started to use aspirin and then their bleeding time was worse their ptt was even longer but it's common sense as i told you before von willebrand disease it's a problem with platelet adhesion aspirins and antiplatelet so it's going to obviously make the disease worse that's kind of common sense then the other thing you can test for is your von willebrand factor antigen or your activity which is going to be decreased or show no platelet aggregation so there's a number of screening tests for von willebrand disease you don't need to know all of them if they mention a von willebrand factor antigen test is decreased obviously she'd be thinking that von willebrand disease the one thing that i'm going to mention because it's unique and i think it's kind of interesting so and that's related to the von willebrand factor activity test so the way that you measure the activity is with something called ristocetin so ristoctin specifically aristocetin cofactor risto cetin was actually an antibiotic we used years ago until we found out that it caused platelet agglutination so we didn't want to use it anymore after that but when you add ristocetin to plasma in a normal patient with normal von willebrand factor it causes the platelets to clump together and you can visualize that so if you add aristocetin to plasma of a patient that has von willebrand disease you're not going to see this platelet aggregation and then we know this patient likely has von willebrand disease so it's just a way we can use this old antibiotic with this terrible side effect for something specifically in our diagnosis so i thought that was kind of interesting that i'd mention as far as treatment pretty simple here so ddavp is going to be your main treatment especially for your mild patients so desmopressin as we went over in hemophilia a causes the release of endogenous von willebrand factor this is going to be the one you're going to use most frequently and likely this will be the answer on the vignette so focus on memorizing ddavp for the treatment of von willebrand disease you also have the option of von willebrand factor concentrates this is really for um patients with type 1 and type 2 disease that have severe von willow brand disease or patients with type 3 because type 3 it's a quantity problem with von willebrand disease and they have very little close to no von willebrand factor so we can't use ddavp in patients who have little to no von willebrand factor like in fact type three or severe types of one and two and it makes sense because ddavp encourages the release of endogenous von willebrand factor well if you have little to no endogenous found willowbrand factor it doesn't matter if you take ddavpp it's not going to do anything and that's why in severe patients or patients with type 3 who have little von willebrand factor to begin with we can't use ddavp we have to use fundamental factor concentrates but most patients you'll be able to so that's what i would commit to memory for treatment just remember ddavp that's the main one now um what do you need to remember for this remember it's a decrease in the quantity or quality of on willow brand factor remember look for your mucocutaneous bleeding you're easy bruising remember this is the most common inherited bleeding disorder and then remember treatment with ddavp that's the main one i'd remember and then you also have the option of von willebrand factor concentrates as another treatment option for those severe patients all right let's move on to factor five lyden so this is a single point mutation in factor five which leads to a hypercoagulable state so factor five is part of the clotting cascade helps form clots by amplifying the production of thrombin thrombin is an enzyme that converts fibrinogen to fibrin to form our fiber and clots anyways factor five helps us form clots that's awesome that's what we want to do but the problem with factor five is he doesn't really have a stop button he just keeps going and going keeps help making more and more clots so he needs somebody to tell him when to slow down so the person that does that or the protein that does that is a protein that comes from the liver called protein c so protein c's job is to go to factor five and tell him all right you've done enough slow down you did a good job factor five no more clotting for now so we don't have clots all over the place well in factor five leiden we have this point mutation on factor five and this point mutation causes um factor five to no longer be able to be what's known as cleaved which is a way of inactivating that's how factor c or that's a protein c inactivates um factor five lyden so he just does whatever he wants he doesn't listen to protein c anymore so think of the point mutation in factor five as like earmuffs nice to visualize it like this so the liver is shooting out protein c protein c is going to factor five and he's like stop no more clots but factor five has this point mutation aka your earmuffs and he's not listening anymore so that's what happened in factor five point mutation aka earmuffs protein c is yelling stop no more clots he can't hear him he's just going on and on and that's why we have this clotting in factor 5 lyden all right so this is your most common cause of inheritable hyper hypercoagulable state so that's important to know because if they ask you a question with clotting even if you just guess factor five you'll probably be right because it's your most common cause the way that i used to remember that it's kind of silly but hopefully it works for you but at least remember factor five lyden stood for frequently forming lumps those lumps in my head are clots so i used to remember factor five liden was the most common cause of your hypercoagulable state frequently forming lungs lumps that's factor five lyden okay uh clinical manifestations so this is going to be venous thromboembolism so your dvts your pe s in real life patients with factor five liden only around five to ten percent of patients actually go on to develop venous thromboembolism but in the vignette they're definitely gonna give you that this patient's gonna have a dvt they're gonna have a pe and then another thing that you may see with patients with factor 5 lyden which i forgot to put under clinical manifestations there but they may also have miscarriages so there's a lot of data showing that factor 5 lyden can lead to unexplained recurrent late pregnancy loss it's assumed this is due to thrombosis of the placental vessels but it's another thing that i remember them mentioning in vignettes it's this history of multiple spontaneous miscarriages and the patient also has a dvt so look out for that factor five line and i'm sorry i didn't list it there but i'm telling you it out loud so remember look for miscarriages and factor five liden in addition to your venous thromboembolism now diagnosis um genetic testing so if you have a patient you suspect factor five light and recurrent venous thromboembolism family history of recurrent uh venous thromboembolism you look for that point mutation as we discussed before and you do that with genetic testing um and you're gonna look for that um that problem with the factor with the with the factor five now before you do genetic testing you usually start with a functional activated protein c resistance test um you do this first if it's positive positive which shows act um protein c resistance then you would go ahead and proceed with genetic testing because obviously genetic testing is much more involved and more expensive so you normally start see if there is protein c resistance and then you move on to genetic testing as far as treatment this is pretty straightforward it's really just going to be anticoagulation so whether this is just prophylactically prior to surgeries or used indefinitely it all depends on the risk factor for the patient so what do you need to know for factor five lighting you need to know that this is a mutated factor five out of control leading to a hyper coagulable state remember this is your most common inherited cause of hyper hyper coagulability remember factor five lighting stands for frequently forming lumps remember you're going to see your venous thromboembolism as well as your miscarriages and then remember you treat this with anticoagulation proteins cns deficiency and then we will wrap it up it's not a lot to know here this is going to be decreased protein c or or protein s leading to a hypercoagulable state so i wouldn't dive too deep into the patho here because they become a little bit complicated but protein c and s they both they both come from the liver they combine with something known as thrombin and thrombomodulin and they cleave and inactivate factor 5 which we just went over but they also cleave and inactivate factor eight more specifically protein c is involved in this protein s is a cofactor but just to make it super simple what i used to remember is that protein s and c stand for stop clots that's what they do they slow down factors five and eight and uh they slow down clotting so the problem is if you have a deficiency in protein c and s you're gonna have more clots you're gonna have a hypercoagulable state because factor five and eight are no longer being shut down or cleaved so that's the issue we have here as far as clinical manifestations same as factor 5 lighting we're going to have our venous thromboembolism these patients are going to be more prone to dvts pes but then we have another thing which isn't only seen in protein cns deficiency but it's more common and that's something known as warfarin induced skin necrosis so when you first start on warfarin it's possible to have this transient hypercoagulable state which can lead to ischemia infarct necrosis because of a clot forming that's why in our high risk patients we actually bridge warfarin for the first few days with heparin or another short acting anticoagulant to prevent this but why does this happen in the first place well there's a few different mechanisms one is just due to how slow the onset is of warfarin but one of the main causes the one that's specific here is actually from a protein c deficiency so let's actually explain a little bit about why that happens so warfarin works by inactivating your vitamin k dependent clotting factors basically all of the clotting factors coming from the liver warfarin shuts or slows them down so that's factors two seven nine and ten but also what else comes from the liver protein c and s so they're also shut down or decreased in quantity from warfarin but the problem is they all have different half-lives particularly protein c has a really short half-life so after just a few hours protein c is already shut down it's not coming back due to the warfarin but your other factors some of your other clotting factors actually have half-lives of two to five days so you have this um this balance issue where there's really no longer your um body's natural anticoagulants like protein c hanging around but then you still have a lot of your clotting factors and that's why you can have this transient prothermic state due to your natural anticoagulants like protein c disappearing early on and this can obviously lead to clots ischemia infarct and warfarin induced skin necrosis due to that protein c deficiency that's again why in these high risk patients we will bridge warfarin with heparin for the first few days to prevent this from happening happening heparin kicks in much quicker and doesn't have this issue as far as your diagnosis you can do a protein c and s assay there's a variety of assay methods that can measure protein c and s activity or levels um diagnosis of protein c deficiency is basically just establishing and documenting a low protein crs level genetic testing is not often used it's not really widely available like we saw in factor five lighting so treatment remember anticoagulation just like in factor five like anyone else who develops a clot anticoagulation is appropriate for patients with protein c deficiency who do as well who develop a thromboembolic event and then you can also um treat with protein c concentrate so often give prophylactically prior to surgery or in pregnant patients around the time of delivery so what you need to know for protein cns deficiency you need to remember protein cns are uh you have decreased levels of protein cns leading to a hypercoagulable state because remember protein s and c stop clots you need to remember your venous thromboembolism your warfarin induced skin necrosis and i explained the patho with the warfarin induced skin necrosis i wouldn't necessarily memorize that though that was just kind of a little bit of extra knowledge for you i don't think it's important to know for the exam though for you to memorize and then remember your treatment is going to be with anticoagulation and protein c concentrate all right let's test your knowledge see what you remembered here uh question one seven-year-old boy presents the office today with significant swelling over his right knee mother states that 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 coagulation studies reveal a prolonged ptt and a plasma factor 8 assay shows decreased levels what would be the first line pharmacologic agent to administer in this patient so that is going to be desmopress and ddavp so this patient has a clear presentation of hemophilia a male gender remember this is excellent recessive remember dr phil hemarthrosis which is the most common manifestation in your ambulatory patients with hemophilia prolonged ptt and then of course a decrease factor eight so we know this is hemophilia a and how do we treat mild cases of hemophilia a that's with desmopressin aka ddavp which increases the release of endogenous von willebrand factor because we know that stabilizes factory in the body question two what is the most common inherited bleeding disorder that's going to be von willebrand disease seen in up to one percent of the population question three a uh 39 year old female presents at the er with lower leg pain and swelling doppler of the lower extremity is performed which 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 line is your most common cause of inherited hypercoagulable states so always be thinking factor five before any of the other ones like protein crs deficiency remember frequently forming lumps and we know this patient had multiple dvts they have a family history of dvts plus miscarriages we know these are all potential problems in factor five line in and we know the most likely cause of the problems this patient's having is a mutation in factor five leading to resistance to it being broken down by protein c question four hemophilia b is a deficiency and which clotting factor remember that's going to be factor nine remember b9 the tumor is b9 and then question five a 52 year old female who was recently started on warfarin for dvt prophylaxis begins to develop necrotic lesions on her legs and feet a deficiency in which vitamin k dependent plasma protein likely led to this presentation so remember that's going to be protein c this patient has warfarin induced skin necrosis remember with the warfarin the reason we bridge with heparin or low molecular weight heparin and our high risk patients is due to that transient prothermic state due to that protein c kind of getting out of the picture quickly and then all of your other um clotting factors still hang around for a little bit longer all right so that um is it i hope that was helpful please let me know in the comments if it's helping you and then please let me know if there's anything you want me to focus on in the future which topics you want me to go over anything like that so thank you so much for listening to the video i again hopefully was helpful and good luck on your pants your panry eors and good luck in pa school