what's up ninja nerds in this video today we're going to be talking about hypercoagulable states also known as thrombophilia again this is part of our clinical medicine section if you guys like these videos they make sense to you they help you please support us you can do it a couple different ways hit the like button comment down the comment section subscribe also go down the description box below there's a link to our website on that website we'll have tons of things that can help you throughout your academic journey things like notes quiz uh banks we have illustrations and so much more so go check that out but let's get into hypercoagulable states all right my friends so when we talk about the pathophysiology of hypercoagulable states it kind of really begs the point of why are we discussing this uh concept of verose triad well if you remember VKOS triad was the triad that determines the risk of thrombosis and that's dependent upon stasis of blood flow endothelial injury and hypercoagulable state so not only can hypercoagulable states increase the risk of a thrombosis within a vein or artery but so can stasis and endothelial injury so it's important to just have a quick recap of again what is stasis it's kind of a where the blood is stagnant and it increases the time for platelet binding to the endothelium so that's really the kind of concept here is it increases the time uh increases time for platelet binding to endothelium so for example as blood is stagnant you have more time especially if the platelets are moving through here to be able to stick to the endothelium and if these platelets stick to that endothelium then what's going to happen well I think you already know what would happen is that these platelets would then start sticking to the endothelium they would stick to one another via the GP2B3As they would release ADP thromoxin A2 and then eventually you would lead to this thrombus formation and then after the thrombus formation you'd have to activate the coagulation cascade which will lead to the fibbrin mesh so the pla plug is primary hemoasis and the fibbrin mesh is secondary hemostasis what I think is really important to remember here is that there's a couple different things that can increase the time right where plates combined and I'd say the most common trigger for this is usually going to be immobilization so this could be immobilization for a lot of different reasons but anything that causes immobilization for long periods of time are going to increase the risk of stasis this could be due to prolonged traveling um flights car rides that are greater than eight hours long bed rest because you had a surgery or bed rest for another reason maybe you have paralysis and you're not able to move and so these are things that'll definitely increase the risk of that contact time endothelial injury is whenever there is a reduction there is a reduction in your anti-thrombotic cytoines um and so you guys got to remember here that there's those cytoines which are called PGI2 and nitric oxide right so normally nitric oxide and PGI2 are supposed to do what well they're supposed to basically inhibit the platelet from wanting to bind to the endothelium right that's what they normally do if this is present but whenever there is dysfunction there's damage to the endothelium you lead to a decrease so you inhibit the release of nitric oxide and process and as a result guess what you're going to do you're going to stimulate the platelets to start doing what aggregating to that site of injury and when they do that they're going to bind with the von wilderbron factor they're going to bind with each other they're going to release ADP they're on a2 lead to the primary hemostasis coagulation cascades going to be activated and you're going to lead to the vibrant mesh which is the secondary hemostasis question is is what causes endothelial injury a lot of different things i'd say the most common one that is important to remember is some type of surgical procedure so surgery is a really big one trauma is another one right i would also say smoking is a really big trigger for this as well but you can understand that endothelial injury can be due to a lot of different things but I would say some type of seizure surgery trauma or smoking lastly is a hypercoagulable state hypercoagulable states this can induce thrombosis but it's interesting it's usually due to a increase in the activity of pro-coagulants so pro coagulants these are clotting factors that want to induce clotting these are clotting factors that want to induce clotting or it could also be due to a decrease in anti-coagulants and these are guys that want to stop clotting all right so they want to again do what they want to I'm sorry they want they want to uh stop the bleeding proc the clotting process right so again anti-coagulants you're trying to stop the clotting process so if I have a hypercoagulable state it could be due to an increase in procoagulants or a decrease in anti-coagulants now let's say here in this particular scenario I have the platelets they aggregate they form my primary hemocatic plug when they form that primary hemostatic plug if I have lots and lots of these procoagulants or less of these anti-coagulants my coagulation cascade is going to go ham and I'm going to start leading to lots of these secondary hemostatic plugs forming so we can see how in hypercoagulable states this can definitely increase the wrong risk of thrombosis because again you're increasing the activity of that secondary heistic plug now when we talk about hypercoagulable states it's important to remember that this could be inherited All right and this is going to be the less common one all right but it is something to think about especially if you have strong family history you have recurrent thrombosis of a like a DVT um or a PE um or also like clots in weird locations like cerebral veins messentic veins portal veins um hpatic veins things like that um so that would be some things to consider but it could be inherited thrombophilia and we'll talk about what these are or it could be an acquired thrombophilia right or it can be an acquired thrombophilia and I'd say most of the cases when we talk about this it's usually going to be acquired now when we kind of go back here hypercoagulable state you're hearing coagulants pro-coagulants anti-coagulants clotting factors it's important to remember your clotting cascade and again this is a basic concept you have your intrinsic pathway which starts with factor 12 he becomes activated by binding to the negative charges on platelets that then activates factor 11 factor 11 activates factor 9 factor 9 and activated factor 8 which is formed by thrombin activating it does what leads to factor 10 10 and factor 5 activate thrombin and thrombin converts fibbrinogen into fibbrin all right so this is that classic intrinsic pathway right and then these really help to drive this process so when a patient is having some type of hypercoagulable state maybe there's an increase in this activity where you're having some type of increase in this fibbrin mesh being formed right you're making more fiber mesh you're causing more secondary hemoasis it could be due to something going on with the intrinsic pathway maybe it's an increase in factor five maybe it's an increase in factor 10 who knows extrinsic pathway it could be the same concept here you have factor three which is tissue factor it can get activated and in the presence of that and factor 7 A these two can also activate factor 10 and so again if a patient has some type of process here where they for some reason increase their tissue factor or increase their factor 7 they can increase the formation of the fibbrin um strands right and if you have more fibbrin you have more fibbrin mesh more plate secondary heistic plugs you're going to get more thrombosis so it is important to understand that we're having some way shape or form a process here all right but I want to dig into this a little bit more and kind of go step by step so we know that a patient can get a thrombus from what reasons stasis of blood flow that's usually due to immobilization for prolonged periods of time or it could be due to endothelial injury smoking surgical procedures anything that's accessing and cutting into that vein or artery that's going to be a problem but the big one that we're trying to talk about today is hypercoagulable states increase in procoagulants and a decrease in anti-coagulants the big procoagulants you're seeing them right here it's factors 12 11 9 8 10 5 and fibbrin right which is the 1A or factors 3 and 7 your anti-coagulants we'll talk about a little bit later but these play a role in this pathway some of those that you'll probably want to mention a little bit later or know could be things like protein C protein S and anti-throbin 3 these are also involved in this and these are in some way there's an increase in the intrinsic activity an increase in the exttrinsic activity and maybe there is a decrease in these proteins and we'll dig into those specific diseases and see how that plays a role but I'm just giving you kind of an introduction so we talk about hypercoagulable states we said that they can be inherited all right inherited is really important to remember and we'll talk about a couple of these but again we said it could be due to increased procoagulant procoagulants or it could be decreased anti-coagulants so if I have more procoagulants which ones am I really kind of thinking about well one of these conditions we'll talk about this a little bit later is called factor five leiden that's one mutation and this can be hetererozygous or homozygous most of the time it's heterero hetererozygous so it's not as severe but it is the most common hypercoagulable state that's inherited the other one is a pro-throen gene mutation so these are the big things that I would like you to remember that are primarily going to increase the activity of what we would say procoagulants it's going to increase the activity of maybe the intrinsic or the exttrinsic pathway and cause this type of process the other one that could be inherited is a decrease in the activity of the anti-coagulant pathways right and this could be due to things like protein C deficiency protein S deficiency as well as anti-throen 3 deficiency so this is the really really important things to remember here so if we can kind of think about this really what it comes down to is factor 5 liden if you go to this pathway you're having a increased activity of factor 5 prothroin G mutation you're increasing the act activity of throen formation protein C and protein S and anti-throman 3 deficiency we'll see a little bit later leads to inhibition of certain types of factors here all right um and so if you have less of them you can't inhibit these coagulation factors so this is really important to remember so we'll talk about these are the big ones there's one other one that we'll mention very very briefly and that's hyper homocyinemia but these are the big inherited ones that I want you to think about for acquired hypercoagulable states this is going to be in a patient who doesn't really have a family history of such we're thinking immune mediated or non-immune mediated now non-immune mediated is actually pretty straightforward and this one you want to think about pregnancy that's a really really big one i would also consider things like oral contraceptives to kind of go handinhand with that because estrogen and progesterone have that ability to lead to this hypercoagulable state um another one could be any kind of malignancy that's definitely something I would also highly highly consider we'll talk about that and when we talk about a lot of these you'll see that there's so many different things that can contribute to this um we'll go over these a little bit later um but we'll talk about some some rare entities in this particular scenario um one of again we'll get into a little bit later but there's some other ones like myo proliferative neoplasia um which is an interesting one where you can have lots of red blood cells and lots of platelets and that can increase your risk of forming these thrombosis but let's at least remember these for now now when we talk about acquired hypercoagulable states the most common reason is usually malignancy so funny enough if a patient has malignancy that really increases the risk of a hypercoagulable state much more so than these inherited thrombophilas and these immune mediated ones but when we talk about immune mediated this could be due to antibodies and these antibodies could be activating procoagulants or they could be activating platelets and so if they activate or they increase the activity of your procoagulants or if they activate platelets what's that going to do i mean think about it same thing like this right you increase your procoagulants decrease your anticoagulants what's your end game here you're going to lead to a thrombus same thing if you increase your procoagulants and activate your platelets you're going to lead to a thrombus because you're causing the platelets to adhere to the endothelium primary heistic plug and you're causing the procoagulants to increase the activity lead to fibbrin leading to the secondary hemostatic plug so we we got this all covered right it's pretty straightforward now it could be auto antibbody mediated and we'll talk about a couple different conditions that could could be due to auto antibodies but in a rare select few it can be due to complement proteins and these complement proteins can maybe activate the platelets and this is rare scenarios where C3 compliments we'll talk about it in what's called P&H proximismal nocturnal hemoglobinia can lead to activated platelets and lead to a primary heistic plug so with that being said we've now discussed okay a patient who gets a thrombus a DVT a PE those are the big ones but maybe they get in weird locations in the cerebral sinus veins or maybe they get in an apatic vein a splanknic vein like I'm sorry a messenteric vein a paddic vein a portal vein these are weird scenarios right most of the time when a patient gets a DVT or PE you think about are they immobilized for some particular reason right prolonged travel bed rest post-operative paralysis or is there endothelial injury did they get a surgical procedure do they heavy smoke or hypercoagulable states especially in this one you really want to be thinking about malignancy pregnancy oral contraceptives sometimes it could be immune mediated i'd say that out of all of these it's going to be one of those you don't always think about and very rarely is it an inherited thrombophilia but what I want to do now is I want to go through all the different types of inherited thrombophilas explain how they lead to a pro-coagulable state go through the types of immune mediated thrombophilas and explain how they lead to a hypercoagulable state and then the last thing I'll do is I'll discuss a couple little things about the malignancy aspect and what I hope to accomplish throughout this conversation is how exactly do we differentiate them let's do that all right so let's talk about inherited thrombophilia patient comes in maybe they have three like they have an episode of I've had a DVT in 2001 2004 2010 so they've had recurrent DVTs or pees that's concerning for an inherited thrombophilia that's one second they come in they say I got a family history my my father and his brother died at a young age or due to a PE like maybe they were like 40 usually less than 45 or 50 years of age with a strong family history of that first degree relative having a clot burden that's enough to say it could be an inherited thrombophilia third is a patient who has clots venus clots in very weird locations usually it's a DVT in the leg right it's usually going to be the big one the femoral the popial the iliac vein something like that um or a PE it's not common all the time to see cerebral venus sinus thrombosis especially apatic vein thrombosis um mezentic or portal vein thrombosis that's not a common entity so if you see those you should think about an inherited thrombophilia right those are three big reasons why I would consider that now when you consider those again you want to think about factor 5 lid mutation as the most common one happens in factor 5 liiden is that most of these patients have a header hetererozygous type of mutation right but what's really interesting here and I think this is more of an MCQ for the step one but they have some type of mutation where it's an R506q mutation and this just swaps out the amino acids in the protein of factor 5 and so what ends up happening is the liver makes this factor 5 right here it is the difference is that now that you changed up the amino acids you make this factor 5 resistant to being degraded so here you have protein C and protein C is good at breaking down factor 5 and factor 8 right so this is an anti-coagulant wants to basically decrease the function of procoagulants and so here's my factor five protein C wants to degrade this but what happens here is that this factor five imagine it like this imagine it's got like this like little spike here um we'll kind of like do it like this and this is due to the change in the structure of factor 5 so because there was a mutation you change the structure and now this protein C isn't able to go and degrade this and so this reaction where you're supposed to degrade the factor 5 doesn't occur and so this leads to a increasing factor 5 levels factor 5 levels and the reason is that it's due to protein C unable to degrade the factor 5 so this leads to protein C unable to degrade factor 5 right and so because of that that leads to these increased factor 5 levels what does factor 5 help to do it helps to in combination with factor 10 do what it leads to increase factor 2 increase factor 2 leads to increase fibbrin formation and if I increase my fibbrin formation what am I going to lead to i'm going to lead to that secondary hemostatic plug and boom I got my thrombosis so that's kind of how we see this kind of process play out is we increase the amount of our factor 5 by preventing it from being able to be degraded because of this mutation that exists so if I cause that mutation that mutation changes the amino acid sequence and it makes it to where protein C is now unable to degrade factor 5 it makes it resistant to degradation pretty interesting prothroin gene mutation is another one now this one is due to a mutation as well this one is a mouthful it's a G20210A mutation and so I'm basically switching one of the nucleotides right guanine forine right and so whenever you do this you change the overall structure of the prothroin and you make it to where the proth thrombin is more active now in that scenario here I'm going to lead to increased proth thrombin right so this is going to lead to an increase uh proth thrombin activity now that's interesting because proth thrombin right let's say here's our liver our liver makes this proth thrombin proth throen is basically factor 2 it's basically factor 2 but it's in the inactive form and so what happens is if I have a proth thrombeng mutation as long as I have the uh particular enzyme present what will happen is is I can convert the proth throen into the active form because here thrombin we needed to be in the active form technically and so if I have high prothroin activity what I'm going to do is I'm going to convert that prothroin into a lot of what thrombin and if I get lots of thrombin that's converted into eventually fibbrinogen into fibbrin and if I get lots of fibbrin what am I going to do i'm going to lead to my fiber and mesh and I'm going to lead to this kind of clotting this hypercoagulable state right so when we talk about factor 5 liden it's a factor 5 that's resistant to the degradation of protein C right due to a mutation changing the amino acid in the protein structure for prothroben G mutation I'm leading to a mutation where you switch a nucleotide that increases the expression of prothroin more proth thrombin means you can make more thromben more fibbrin more clotting okay that increasing clotting or that thrombosis that we'll see will then present clinically in the form of a DVT a PE or unusual clot location and in some circumstances um we can see these patients having pretty bad you know recurrent thrombosis with hyperomocymia this one's kind of an interesting one you don't see this a ton but what we do consider this in is in patients who have again an inherited thrombophilia uh and usually they present with arterial and venus clots so it's a combination usually patients with protein um I'm sorry factor 5 liden prothroen gene mutation anti-throman 3 protein CNS deficiency they only res really present with venus thrombosis but hyperomocymia is one of those rare uh types of inherited thrombophilas where a patient could present with both arterial and venus thrombosis but um this pathway is really dependent upon folate actually so you need folate in order to be converted into dihydropholate and then into tetrahydropholate then 510methylene tetra hydroolate and then 5methyl tetrahydropholate now there's an enzyme that's really involved here and this enzyme is called u methyl tetrahydropholate reductase and it's supposed to drive this step the conversion of 510 methylene to 5methyl tetrahydropholate and the reason why that's important is fivemethyl tetrahydropholate is needed in order for you to kind of do this particular process so I want to go from fivemethyl tetrahydroofolate to tetrahydropholate i want to give off a methyl group and when I do that I do that by another reaction and I donate that methyl group to another molecule and this molecule is called homocyine and I want to convert it to what's called methionine which is a type of amino acid but if a patient has a mutation right and so now they don't have the presence of this methyl tetrahydropholate reductase so now let's take this out and let's say that this person if it's inherited if it's inherited it is a mutation in the methyl tetrahydropholate reductase enzyme so now we're going to introduce this now ready if I don't have the enzyme right here I'm going to inhibit this step i'll have less of this because again I don't have that methyl tetrahydropholate i have less of this if I have less of this I'm not going to be able to undergo this reaction so this reaction will be inhibited if this is inhibited I'll make less of methionine and I'll build up homocyine now homocyine is problematic because it's pro-inflammatory and what it likes to do is is it likes to activate factor 5 and it likes to activate um uh it likes to suppress anti-throen 3 so it'll increase the activity or it'll stimulate factor 5 and it will inhibit anti-throen 3 so now if I go ahead and I stimulate factor 5 I'll increase what that formation of factor 2 thrombin and then I'll increase the formation of fibbrin and if I increase the formation of fibbrin I'm going to lead to that fibbrin mesh baby yeah now if I suppress or I inhibit anti-thrombin 3 guess what anti-throman 3 does it primarily decreases the production of thrombin it's anti-throen and so what will happen is I will do what it naturally wants to suppress thromben production but if I inhibit anti-throman 3 I will therefore decrease anti-throman 3 levels and I'll release it from inhibition and so instead I'll lead to the increased activity of thromben and then the fibbrin mesh and then we'll get that thrombosis so in patients who have hyperomocymia if it's inherited it has to do be due to a mutation here in certain situations it could be acquired and this is usually in folate deficiency or B12 deficiency but that's the big things to remember so the next component here is okay we talked about factor 5 liden a basically hardy factor 5 that can't be broken down by protein C elevates the thrombin levels the fiber and you get a clot prothroin gene mutation you get a mutation that leads to increase prothroin activity you get more thrombin you get more fibbrin you get the fibbrin mesh hypomocyinemmia a mutation in an enzyme that helps within the what conversion of fivemethyl tetraety hydropholate to tetrahydropholate and homocyine to methionine you end up with increased homoy you increase your factor 5 you suppress your anti-throman 3 this next one is protein CNS deficiency so what's really important to remember is that the liver synthesizes what's called protein S and protein S is really important because what happens is protein S is supposed to act as a co-actor it basically it's a co-actor so let's write this down it's a co-actor for protein C so imagine this if a patient has a deficiency in protein S what will happen to the activity of protein C I'll end up with decreased protein C so if I have decreased protein S I'll have decreased protein C so you see how protein S deficiency is pretty much tied directly to the protein S deficiency all right so here's the important thing if a patient has a protein S deficiency they won't form protein C if a patient has protein C deficiency they just won't make protein C so you get the difference here right so protein S deficiency it's your liver is not making protein S and therefore you're not helping to activate protein C protein C deficiency you're not producing protein C whenever there is a decrease in protein C protein C is designed to inhibit procoagulants so it wants to inhibit procoagulants and this is going to be factor 5 and factor 8 but if I have decreased protein C am I going to be able to inhibit factor 5 and factor 8 no and so as a result they stop becoming degraded and inhibited and you increase their activity factor 9 um I'm sorry factor 8 and factor 9 lead to the formation of factor 10 factor 10 and factor 5 combine and help to activate thromben right and then thrombin leads to the formation of fibbrin so when you think about this factor 9 will really help to activate factor 10 especially in the presence of what's the other factor here that you would need factor 9 and then factor 10 and factor 5 will help to lead to the formation of thrombin thrombin will lead to the formation of fibbrin fibbrin will lead to that fibbrin mesh and therefore you will get a thrombosis so that's the big thing that I want you guys to remember here okay so I'm just trying connect the dots here for you so when a patient has factor 5 liden they have resistance to breakdown from protein C if a patient has protein C and S deficiency they can't break down factor 5 and factor 8 so they go unregulated and increase clot formation if a patient has a prothroag mutation they increase their prothroin they make more thromben more fibbrin if a patient has increased homocyine they suppress anti-thrombin 3 and increase factor 5 so these are really really important things to remember so I'm going to end off with the last inherited one the last inherited one here is anti-throman 3 deficiency now really really important thing to remember protein CNS deficiency and anti-throman 3 deficiency have these like I don't want to say pathonneummonic but close things that if you see this on the vignette you got to remember it and I think this is really important to remember if a patient has protein CNS deficiency I would look at this in a patient who gets a patient with warrin induced skin necrosis so you're probably like wait what it's a really really rough condition the concept behind is actually quite interesting where if you for example if a patient takes warin if they take warphin what warin does is it acts on the vitamin K epoxide reductase enzyme present in the liver and what happens is warin is supposed to produce uh it's that vitamin Koxide reductase enzyme is supposed to lead to the synthesis of factors 2 7 9 and 10 as well as protein C and S if you take warphin you suppress that enzyme if you suppress that enzyme you decrease the production of all of these so these levels fall and these levels fall but because protein C and S have a very short half-life they fall pretty quickly what happens if you drop your protein C and protein S levels you increase thrombosis so in the first couple days in the first like 3 to 5 days until these levels start to kind of like drop the patient's super hypercoagulable so in the first three to five days they are hyper coagulable and this is normal this is normal that's why whenever you give warin you try to bridge it with hepin but now take into consideration a patient has protein CNS deficiency they're already deficient in protein CNS you give them warerin and then guess what you do you suppress their protein C and down even more they got none of this they got no ability to uh basically inhibit factor 5 and factor eight these things go haywire and they clot and they end up with that skin necrosis which looks a little bit like this so it's really important to remember this high yield fact with that being said anti-throman 3 deficiency when you see this one it's usually almost always presented in the vignette where a patient has hepin resistance so let me let me explain what that means patient comes in with a DVT PE you put them on Hepin and their PTT never gets to therapeutic levels in other words you never get that PTT to where you're basically kind of like within the range that you want to prevent them from getting that clot bigger and bigger and bigger because you're trying to prevent clot propagation with heperin if I see them on super heavy high doses of heperin and that PTT is not budging definitely go thinking about anti-throman 3 deficiency so that's really really important to remember so the liver makes anti thrombin 3 right so if patient has like cerosis they can also have an acquired cause of anti-throman 3 deficiency what's another disease that can actually just as a side note I'm not going to draw it up here but if a patient has urinary loss of anti thrombin 3 nefertic syndrome right so nefertic syndrome can actually cause anti-throman 3 deficiency and cause hypercoagulable states and they get renal vein thrombosis that's another important one to remember so write that down nefotic syndrome but a really really big thing here is in a patient who has anti throbman 3 deficiency they have a mutation that leads to a decreased production of anti-throman 3 so I'm going to have decreased anti-throin 3 levels Anti-throman 3 is primarily designed to be able to suppress the activity of what factors 9 factors 10 and the biggest one is thromben and so if you think about this he's supposed to suppress all of these all of these want especially factor 10 so factor 9 and 8 will activate factor 10 factor 10 and factor 5 will activate thromben but the biggest thing here is that thromben is which is what factor two factor two wants to do what activate fibbrin that's what it wants to do and if you get that fibbrin you're going to form that fibbrin mesh baby and if you get that fibbrin mesh you're going to get that secondary hemostatic plug and you going to get that thrombosis so that's the big thing here so if I suppress anti-throman 3 then what do I do i no longer inhibit these factors instead they'll become stimulated their activity will go up and I'll increase the formation of fibbrin and again these will both eventually lead to what these will eventually lead to an increase in thin I'm not going to go through the whole pathway it's excessive at this point but you get the point that anti-throman 3 deficiency does what it basically works by suppressing thrombin normally anti thrombin 3 works by suppressing thrombin factor 10 and factor 9 but if you have a deficiency In anti-throman 3 you can no longer suppress them they become activated and they increase clot formation so now we can kind of see how patients become heperin resistant anti-throman 3 deficiency they're deficient in anti-throman 3 what's heperin supposed to do heperin is supposed to increase anti-throman 3 right so we know that hepin Hepin is supposed to do what well that puppy is an anti-coagulant it wants to increase the anti-throman 3 that's it that's what it wants to do it wants to increase this right that's the normal mechanism this is a normal mechanism of heperin but guess what happens right this is the MOA the mechanism of action of heperin but in this scenario guess what happens you have deficient levels so if you give hepin it won't matter it's not going to increase it enough to be able to get to the point where you can suppress these factors and they're still going to have this thrombosis factor or they're still going to have that PT PTT that just won't get where you want it to go that's the big thing to remember for this okay at this point we've covered the inherited types when would you do this strong family history first degree relative less than 50 they got a DVT PE recurrent VTs you've had two three four different DVTs or pees or you got a clot in an unusual occasion brain hypatic vein portal vein messentic vein now that we've done that let's talk about the acquired causes all right so now let's move on to the causes of acquired thrombophilia or an acquired hypercoagulable state as I told you most of the time it's malignancy more often than not that's going to be the biggest kind of trigger or risk factor for an acquired hypercoagulable state but in some scenarios it could be immune mediated which we'll talk about is antifhospholippid syndrome hyperinduced thrombocyopenia and peroxism nocturnal hemoglobin another one that's acquired that's non-immune mediated besides malignancy is pregnancy and oral contraceptives again don't forget those but antifhosphippid syndrome is going to be one of those that they love to test there's a couple different reasons why one is that not only can they present with recurrent thrombosis but they can recur present with recurrent um spontaneous abortions that's because if you get thrombosis if they occur in the placental vessels you can thrombose the placental vessels that can lead to placental infuctions and then you then lead to unfortunately a non-viable fetus because you're not able to supply the oxygen the nutrients that you need to the fetus so this can definitely lead to placental thrombosis which can lead to I'd say the biggest thing is greater than or equal to three spontaneous abortions at less than 10 weeks gation so usually in the first trimester right this is the big thing to remember if it is one like unexplained spontaneous abortion greater than 10 weeks you could also consider that for antifhospholippid syndrome but this is the big thing to remember so greater than equal to three spontaneous abortions at less than 10 weeks gation think about antifphospholippid syndrome especially if they sometimes present with this weird like lacy type of appearance to their skin called levido reticularis which looks a little bit like this so if I see that I see recurrent spontaneous abortions or recurrent thrombosis I'm going to think about this one the other thing is antifphospholippid syndrome can occur primary in other words we don't have a great reason or it could be secondary and often times this is commonly associated with what's called systemic lupus arithmettosis so it's most often seen with SLE all right so in this patient they they produce auto antibodies right they make these auto antibodies so the plasma cells make these auto antibodies and there's different types one is called lupus anti-coagulant another one is called anti- cardiolipin antibodies and the last one is called anti- beta 2 glyco protein antibodies now these antibodies are quite interesting and the reason why I say that they're quite interesting is that they can do a couple different things one of the things that these antibodies can do is that they can act on platelets so they can stimulate these platelets they can activate them and if you activate these platelets what is going to happen these activated platelets are going to get consumed to make primary hemostatic blood so now these platelets are going to be super activated they're going to be consumed and they're going to start going in here and binding onto the endothelial lining and leading to my primary hemostatic plug that's one way and this can actually lead to if you activate the platelets and consume them enough funny enough this can actually lead to potentially if it's consumed enough it could lead to thrombbo cytoenia so definitely consider that in a patient who has thrombocytoenia think about antifospholipid syndrome especially if they have recurrent thrombosis or recurrent abortions the other concept here is that these auto antibodies they tend to act on uh the glyoproteins particularly that are present within our anti-coagulant activity and so what they'll do is is they will actually inhibit these particular proteins and this is going to be things like anti-throman 3 and protein C and S so by doing that think about this if you inhibit anti-throman 3 that's going to lead to what you're not going to be able to suppress thrombin formation you're not going to be able to suppress factor 10 you're not going to be able to suppress factor 9 if you decrease protein C and protein S are you going to be able to inactivate factor 5 and factor 8 no so what ends up happening with this is a terrible terrible thing which is I end up with a increase in a bunch of different things one is thromben the next one is factor five another one factor nine factor 10 so you see the whole problem here and then also I I should have added this one in here before the nine but two five 8 9 and 10 and again anti-throin 3 is supposed to suppress thromben factor 9 and factor 10 if you don't have that you're going to end up with increased thrombin increase factor um 9 and increase factor 10 protein CNS is supposed to suppress factor 5 and factor 8 if you don't have protein C or protein S you'll lead to an increase in factor 5 and factor 8 by doing this you're going to increase the formation of what the common pathway leading to fibbrin and that fibbrin is going to lead to that secondary hemostatic plug which is going to lead to that fibbrin mesh and that's going to lead to your thrombosis and this can occur in the veins this can occur in arteries so this is a really really bad one antifphospholipid syndrome now it is important to remember that these antibodies you need at least one of these to be positive right so I need at least one of these to be positive at least twice so in other words I have to check these antibodies let's say that I have a patient who has comes in they've had a bunch of abortions they got clots they got they got livita reticularis i test the antibodies one of them comes back positive 12 weeks later I got to test it again to see if it comes back positive if it does and they have the laboratory and the clinical criteria they meet the diagnosis of antifhospholippid syndrome another really important fact that they love to test for on the exam is lupus anti-coagulant is an antibbody when you put it into a blood tube so in vitro uh and you actually look at this antibbody what it does is is it actually causes the PTT to be prolonged it acts like an anti-coagulant and so what has to happen is you would say "Okay cool well the PTT is prolonged what do you naturally do when PTTs are prolonged you do a mixing study you add in normal plasma and see if you're replacing whatever factors they're deficient in or if they have an inhibitor so if you give them normal plasma what will happen after a mixing study nothing because they're not deficient they have an inhibitor so you'll have a no normalization so if you do a mixing study you'll have a increased PTT after a mixing study so what do you truly have to do in order to see if that PTT normalizes you have to add whatever these things like to bind to phospholipids so if you bind if you throw phosphoipids into the test tube after you did the mixing study and it normalizes that's also really suggestive of antifphospholipid syndrome so adding that in there if you take after the mixing study you add some phospholipids to the mix so let's say that I add in these phospholipids then what that's going to do is that's going to cause the PTT to start to normalize and that's super suggestive of antifhospholippid syndrome all right now anti-cardipin antibbody a really important point for this one is that when you test uh patients who have antifhospholippid syndrome and this antibbody comes back positive if you also test them for syphilis it can cause a false positive for syphilis false positive for syphilis uh specifically like the RPR kind of testing so false positive for syphilis with this being said antif phospholipid syndrome is the one that's going to be tested the big things to remember recurrent spontaneous abortions at least greater than or equal to three of them less than 10 weeks um gestation also recurrent venus thrombosis that could be due to a DVT a PE you can even get arterial thrombosis if it's a catastrophic and these patients if they have that and they have one of these antibodies that are positive twice at least 12 weeks apart you meet the diagnosis all right that's the big things to take away from this all right the next one is hepin induced thrombocyopenia this one I don't want you to go too crazy about but I really want you to think about this in a patient with heperin use plus low platelets plus thrombosis and this can this one's bad man this one can occur in arteries or veins just like in antifphospholipid syndrome so what happens is you give the patient heperin all right so here's your heperin molecule in this pink what heperin will do is here's a platelet and on the platelet there's a molecule here called PF4 plactor 4 hepin will go and bind with platelet factor 4 and so now you get this complex this is a heperin platelet factor 4 complex this is kind of amunogenic and so what happens is you have these antibodies against hepin and platelet factor 4 and what they do is they go and they bind onto that complex when you do this you activate the platelet and so now that my platelets are activated guess what I'm going to do i'm going to consume the platelets to make thrombus and so now I'm going to consume these platelets and these little puppies in here are going to start binding on to the actual wall of the endothelium leading to this primary hemostatic plug eventually the fibbrin mesh will begin to form and I'll end up with a thrombosis all right so this is a patient who can get thrombosis thrombocytoenia after hepin used within the past 5 to 15 days all right so antifhosphippid syndrome female young SLE recurrent spontaneous abortions less than 10 weeks gestation positive antibbody testing right for the antifhosphoipid antibodies hepin induced thromboc thyroidenia hepin exposure thrombocytoenia and thrombosis all right big thing here usually for this one what we like to do is we like to first test what's called the PF4 antibodies so we'll literally test these antibodies that are against the heperin and the pf4 and see if those are positive especially if they have a high probability of having hit um or hepin induced armocyenia in other scenarios what we can do is we can actually take these patients and do what's called a serotonin release assay which I'll talk a little about a little bit later in the diagnostic section all right but usually they'll have an elevated serotonin release because what happens is these auto antibodies are activating platelets and what happens when you activate platelets they release ADP thrombox 82 and serotonin so if I'm activating them I'm going to have a high amount of serotonin all right we come down here the next one is proxismal nocturnal hemoglobinuria so this one I really want you to think about this one in a patient who has dark urine in the morning in the A.M i want you to think about this in a patient who has homolysis so how would I see if a patient has homolysis they would have an increased LDH a decreased hptoglobin some shistytes right right and then the other thing is I'd have odd locations for Venus throbo emolism what the heck does that mean cerebral venus sinus thrombosis in the brain i would end up with a portal vein thrombosis apatic vein thrombosis just weird locations so if they have dark urine in the morning signs of homalysis and on top of that unusual weird locations for a clot think about P&H now with P&H I don't want to go too crazy because we talked about this in the anemia lecture there is a pig a mutation so there's a pig a gene that gets mutated what happens is when you mutate that it leads to a decreased expression of this protein so now what happens is I don't produce this molecule here i end up with a decrease in what's called the GPI anchor that GPI anchor is supposed to bind these two proteins here which is called CD55 and CD59 these are cluster differentiation proteins if I don't have the anchor can I bind on to these proteins no and if I can't bind onto these proteins do I have enough of these no you know what these proteins are supposed to do they're supposed to inhibit compliments if I don't have them can I inhibit the compliments no so what happens i activate them sons of guns so now the C3 compliments are activated and these sons of guns these little sobs are are relentless and what happens is when these become activated they go and they bind onto the red blood cell and they trigger homalysis of the red blood cell all right so they trigger a compliment mediated homalysis they cause the membrane attack complexes right then what happens is what's the most primary molecule found inside of our blood cells hemoglobin so what's gets released hemoglobin that hemoglobin gets released into the bloodstream when you get a lot of hemoglobin into the bloodstream guess what it binds to nitric oxide when you bind up nitric oxide what happens to the free circulating nitric oxide it decreases so you decrease the free nitric oxide why is that important if you decrease the free nitric oxide guess what nitric oxide is supposed to do you guys remember this in a normal endothelial cell it releases what's called PGI2 and nitric oxide which does what it inhibits the platelets it's supposed to suppress them right it's supposed to suppress them and prevent them from being activated but if you have less nitric oxide what happens if I don't have enough of this i'm going to stimulate the platelets and then what's going to happen oh man I got activated platelets baby my platelets are super activated and if I get these activated platelets in the right area guess what they're going to do they're going to my stuff up they're going to come in here and they're going to start causing that primary hemostatic plug and they're going to lead to a good thrombosis in an odd unusual location and that's the big difference so they'll get homoysis and that's where you'll get all the increased LDH right so that's where you get the right the increased LDH the decrease heptoglobin right so the increased LDH the decrease haptoglobin and then the shistytes right because you're busting these things open right but the big thing to really take away here is the mechanism by how we actually cause thrombosis all right that's this one the Next one is malignancy so we can actually see this in two different types of malignancies one is called myop proliferative neoplasia and one is just your solid organ so one is like a solid organ malignancy and this other one is called milo proliferative neoplasia this is a type of like hematic malignancy essentially now solid organ malignancies they're actually a lot easier usually for example if a patient has lung cancer um or if they have something like pancreatic cancer especially adnocarcinoma um let's actually write that down adnocarcinoma these carcinomomas funny enough have the ability to secrete tissue factor what's tissue factor factor three and so if they increase the expression of factor 3 guess what happens factor three and then combination with factor 7 lead to factor 10 factor 10 and factor 5 lead to factor two factor 2 converts one into 1 a and then what do I get i get my fibbrin mesh so these two will combine to activate factor 10 these will combine to activate factor two fix this up a little bit and then factor two will convert factors one into 1 A which then this leads to that beautiful what we'll already have the plate plug what will this help with this will help with the fibin mesh all right so that's the big thing here here so when a patient has pancreatic adnocarcinoma big thing to look for is the patient with abdominal pain right maybe some nausea but you know what else they like to do they like to test the CA19 um kind of like tumor marker but another thing that they like to do is um they like to look for what's called migratory superficial thrombophilitis these red inflamed veins that you can see appearing on their arms all right that's one thing lung cancer look for specific signs cough shortness of breath hemoptsis uh things of that nature all right and it's really important to remember this because we like to do age appropriate cancer screening and a patient who has recurrent thrombosis and we haven't found an inherited or other type of acquired cause you really want to think about maybe a chest X-ray or a CT scan now with myo proliferative neoplasia these are weird so you have like um like a myoid stem cell and these are supposed to help to make a a bunch of different cells one is red blood cells another one's platelets if a patient experiences what's called a Jack 2 mutation so they have a Jack 2 mutation this mutation will lead to a hyperp proliferative state then what's going to happen is I'm going to stimulate proliferation i'm going to increase the proliferation of that myoid cell line of cells and so what's going to happen is man these this bone marrow is going to be pumping out red cells or pumping out platelets and so what's it called when you have lots of red blood cells polyythemeia and if it's due to a bone marrow problem it's called polyythemeia vera and if you have lots of platelets it's called thrombocytosis but if it's due to a problem with the bone marrow where it's actually a mutation in this scenario it's called essential thrombbo sytheia now in these scenarios we consider these to be a myop proliferative neoplasia now this one polyythemia vera will increase the viscosity of the blood and that just predisposes it to sludging up the blood and definitely increasing the risk of thrombosis not via the mechanisms that we've talked about funny enough but it does increase viscosity which can increase thrombosis essential thrombocythemia that basically increases the number of platelets which can also increase the viscosity but if I increase the viscosity there that can definitely cause this but also I have more platelets that can potentially precipitate a platelet plug formation either way I'm getting thrombosis so when I talk about these the way that I want you to start forming frameworks with a thrombophilia or hypercoagulable patient is they have DVTs or pees that are recurrent they have recurrent spontaneous abortions they have a strong family history of a family member who's young who's had these clots or they have again clots in unusual locations is it inherited is that the case check for protein C factor 5 anti-throman 3 and again check for that prothroin G mutation big things to remember for the high yield for anti-throman 3 look for a patient who's not responding to heperin they're resistant to it for protein CNS deficiency look for a patient who gets put on warin and they get really bad skin necrosis for antifphospholipid syndrome look for recurrent spontaneous abortions but again you need to have at least two times where these antibodies that we talked about are positive for all of these other ones they can be present but the most common one in true clinical reality is going to be malignancy this increases the risk of hypercoagulability so many fold so really remember these all right we talked a lot about this stuff let's now move into what are the potential presentation or complications of a hypercoagulable state all right so we've talked a lot about the pathophysiology of hypercoagulable states what are the big ways that these patients will present so the biggest complications is the thrombosis itself but it can occur in veins and it can occur in arteries and veins it's important to remember especially in the clinical vignette which one tends to predispose more towards the veins and which ones can involve both and how these will actually look so more common than not you'll have a clot in some type of deep vein in the leg that's usually called a DVT look for pain swelling and asymmetrical swelling at that usually of a lower extremity and if you can you get that positive home enzyme when you dorsif flex another one is that DVT could break off and if it breaks off it could move into the right atrium the right ventricle and it can get stuck inside of a pulmonary artery and that is called a pulmonary embolism for this if a patient gets a PE a pulmonary embism you want to look for tacoc cardia typneia you want to look for any evidence of dysnia increased work of breathing and I would even look for episodes of hypoxia as well the next thing is and this is the unusual locations is a clot somewhere within like a cerebral sinus vein and so this is called cerebral venus sinus thrombosis for this you really want to watch out because this can actually cause a really really bad headache it can even cause seizures because it can irritate the cortex sometimes they can hemorrhage or it can cause a stroke and a big thing is it'll cause a lot of increased ICP and so you can see potential intraanial hypertension features as well the next one is you can get a clot inside of the hpatic vein and this is called bud kiari syndrome all right definitely when you hear this you should think about something like the polyythemeia vera essential thrombocythemia proxism nocturnal hemoglobinuria right things of that nature the other one is it can occur in the portal vein so this is called portal vein thrombosis and then here you could get a messenteric um I'm sorry that's the splenic vein you don't usually get that one there but you can also get a inferior messentic or superior mesenteric vein thrombosis and so I would definitely be on the lookout for some type of messenteric uh thrombosis blood kiari syndrome which is a hpatic vein thrombosis usually that will present with right upper quadrant pain right you may even develop some hpatomegaly some increased LFTs portal vein thrombosis will lead to portal hypertension so it'll lead to splenomegali it'll lead to ascites it can lead to potentially um esophageal veraces and it also can lead to a lot of problems such as again swelling of some of the venus structure so it can lead to a worst case scenario it can potentially lead to a bowel obstruction bowel edema and then mezenteric thrombosis especially if it's an acute one this can actually cause acute bowel um acute eskeemic necrosis of the bowel so acute messenteric eskeemia and so these are really really important things to remember so pain out of proportion with an elevated lactate level maybe even a risk of bowel perforation and sepsis is big with this one so if a patient comes in more often than not it's going to be a DVT or it's going to be a PE rarely will it be a cerebral venous sinus thrombosis or these abdominal vein thrombosis but if it is the more common ones to see that are going to be associated with primarily venus thrombosis on its own it is worth remembering that it's going to be factor 5 liden it's going to be pro throen gene mutation it's going to be protein C and S deficiency and it's going to be anti-throen 3 deficiency anti-throen 3 deficiency so if a patient has recurrent venus thrombosis only you really want to think about these but if a patient has arterial and venus thrombosis so in other words not only do they have a DVT history a PE history maybe not just a cerebra venous sinus thrombosis messentic portal hpatic vein thrombosis but they can have arterial thrombosis maybe have a coronary artery and they can develop a MI or of a card a corateed artery and they can develop a CVA so they can end up blocking off the blood flow to the to the brain or of the lower limb and so this can lead to acute limb eskeeia and so really watch out for myioardial eskeemia or infarction cerebrovascular accident and acute limb eskemia and again it's not just arterial it's arterial and venus so they can get both of these which ones most commonly cause both presentations in that scenario you think about the acquired ones so you think about anti- phospholipid syndrome the next one is I would think about peroxismal nocturnal hemoglobinuria and hit i would also definitely uh be considering one other inherited type the other inherited type here would definitely be the hyper homocyinemmia and the last thing is malignancy with all of that being said you're noticing a trend that most of the causes that lead to arterial and venus is the acquired causes with the exception of hyperhomocyinemmia and the ones that primarily lead to venus clots are going to be the inherited ones except for hyperomocanemia again I would add one little exception and it's remember that P&H and malignancies especially because we're we're talking about a couple different ones here this could be the MPN the myop proliferative neoplasia as well as solid organ the MPN's and P&H cause these types of weird clots so in these weird unusual clots definitely don't forget about this one and definitely don't forget about this one all right all right patient comes in with a thrombus you have to discern if it's primarily venus or if there's venus and arterial from there once you've determined that there is a thrombus if there is a recurrent thrombosis recurrent spontaneous abortions strong family history of thrombosis at a young age or clots in unusual locations work up the patient for thrombophilia do the inherited panel which we talked about here with the exception of this and then work up the acquired causes especially in certain types of risk factors antifphospholippid syndrome P&H hit and malignancy all right let's talk about the diagnostic approach let's say you have a patient coming in and you want to determine if they should get screened for a thrombophilia whether it's an inherited or it's an acquired these are the things that you need to remember they have to have an unprovoked clot at a young age so if they have a DVT or a PE and they're less than 50 and they have no risk factors for stasis no risk factors for endothelial injury then you can consider testing them another one is recurrent clots if a patient came in they had a DVT a year later they have another DVT a year later after that they had a PE you should definitely be testing them for an inherited or acquired thrombophilia if they have thrombosis in really weird locations that normally should not happen with stasis that should normally not happen with endothelial injury if that is happening you really want to think about malignancy you really want to think about uh proxism nocturnal hemoglobinary you really want to think about some of these hypercoagulable states all right recurrent spontaneous abortions this is actually really important because this is actually placental artery thrombosis so you're actually what happens is you get clots that form within the placental arteries that leads to placental insufficiency and then that's why these patients have spontaneous abortions if you hear that again remember anti-phospholipid syndrome and a strong family history if a patient can state my mother had a DVT or a PE at 30 or they had recurrent DVTs or pees or they had a stroke at a young age you can start thinking about these hypercoagulable states all right now you'll get an inherited thrombophilia panel you'll check their factor 5 right you'll check their proth thrombin you'll check the protein CS anti-throman 3 you'll check their hyperomoc you'll check their homoyine levels all of those things will happen it's just you have to be careful you you really can't be screening for thrombophilia if a patient has an acute thrombosis or they're on anti-coagulation because it can skew the results the only exceptions to this is is really just factor 5 lid prothrog mutation these are the only two that you can truly test when a patient has an acute thrombosis or they're on anti-coagulation so you actually have to wait until that resolves and then you can test them for these potential thrombophilas all right it's actually quite interesting when you look at the risk of people who have like DVTs or pees and them having an inherited thrombophilia it is such a small percentage and so it's really important to know that we don't want to um expose the patient to unnecessary testing if they don't need it all right so unprovoked recurrent weird clots recurrent spontaneous abortions and a strong family history get an inherited thrombophilia panel the only time you should actually say ah maybe I should wait is if they have acute thrombosis or on anti-coagulation the only diseases that if you likely think that they could actually have is factor 5 lightin and prothroin mutation so the only ones that if you do the testing they're the only ones that if it came back positive it would be accurate all right if you get a positive inherited thromophilia panel it's just a matter of which part of that was positive all right so if I told you that they have a decreased um what's called activated protein C sensitivity what would that mean oh okay that would be factor 5 lighten oh I remember why because in factor 5 lighten the protein C couldn't break down the factor 5 that's why it's important if I see G20210A mutation on the PCR you think prothromen mutation if I have hyper homocyinemmia boom if I have decreased protein C activity protein C deficiency decreased protein S activity protein S deficiency and decrease anti-throman 3 activity anti-throman 3 deficiency so these right here are pretty simple it's just a matter of remembering that this is the specific thing that we're looking for we're not actually looking for increased factor 5 levels we're looking at activated protein C sensitivity it's going to be low and factor 5 liden and you're going to look for the specific G20210A mutation for proth thrombin G mutation now if I don't have a positive inherited thrombophilia panel I could still have an acquired one right so that's when I want to test for the most common one which is the antifphospholipid syndrome so I'm going to get that antifos lipid antibody panel do you guys remember which one it was again you got to do these where you check the antibbody studies and again you have at least one of the three on these on two occasions 12 weeks apart really really important you have to have positive antibodies for at least one of them all right one of those three on two occasions 12 weeks apart to truly make the diagnosis so you're looking for the lupus anti-coagulant you're looking for the antiardipin or you're looking for the anti beta 2 glyoprotein antibodies to be positive if you get at least one of those three positive two times 12 weeks apart and you have the potential screening criteria already where they had recurrent spontaneous abortions or VTE all right you you've probably got antifphospholipid syndrome all right the other thing that I would say that is more miscellaneous testing if you come up with a negative inherited thrombophilia panel and you get the antifphospholipid antibbody panel is look at the patient's history to see if you would do other testing so for example if I had a patient who had heperin use and they have thrombocytoenia and they have clots I would get a pf4 antibbody and serotonin release assay to confirm hit um if I have a suspicion of proximal monoconal hemoglobinia dark urine in the morning homoleysis um then I may get a flowcytometry to look for that decreased CD55 and fit 59 if I have a suspicion of MPN because they have really high hemoglobin like in polyythemia vera or really high platelet count such as an essential thrombocythemia I'd get a jack 2 mutation on their PCR and see if that comes back positive and if I have a suspicion of a cult malignancy this is really really important then I would do an age appropriate cancer screening chest X-ray to look for lung cancer CT abdomen pelvis to look for a potential pancreatic adnocarcinoma okay all right so when we talk about treatment here we really have determined okay does Does the patient have an inherited or an acquired thromophilia i've done that based upon the screening to know when I should test for it i know when I should really be careful to not really interpret the results as being accurate if they're on anti-coagulation or if they have an acute thrombosis there's two exceptions i can know which one is positive based upon the results of that thrombophilia panel if it's a negative inherited thrombophilia panel I want to test for antifhospholippid syndrome and based upon their history and the clinical vignette I'll know when I'll test for other potential miscellaneous causes so treatment here really depends upon if the patient has thrombosis or not if they have an acute thrombosis you have to manage that and that's usually initiating anti-coagulation usually this is dependent upon the patient having hit or not which one you'll determine if the patient has hit which is a type of hyperquagial state you don't give classic medications that you would give which is Heperin in this one you give the non-ommon medications that we don't often utilize which is your IV direct thromen inhibitors this is our gatriban or balerudin if they don't have hit as their cause of thrombosis then you give them hepin usually it's low molecular weight is the common one or unfractionated hepin which is usually given in a drip now if they have a thrombophilia the next component here is do we initiate long-term management for this patient so we get them started to help actually prevent the clot from propagating so we'll start them on either Hepin or or gatraban then from there we may have to continue anti-coagulation outpatient for about three to six months and then maybe some patients you have to continue antiquagulation for the rest of their life the long-term management depends upon the underlying type of thrombophilia for an inherited thrombophilia you can do a doax so your direct oral anti-coagulants this could be debigotran which is your thrombin inhibitor or you can do your factor 10 inhibitors which is going to be your um a pixaban and riveroxaban you could also consider warfin it really just is whichever option is best for anti-hostal lipid syndrome that one is explic explicitly warin all right has to be warrin for this one for malignancy we actually prefer low molecular weight heperin if we can and then for P&H or MPNs this is actually a problem with an immune issue we actually have to address the immune process or the malignancy process and so we either need to give something to kind of suppress this or suppress this so what we actually do is we say let's let's suppress them and if they have P&H we actually give them something called echalysismab and echalysismab is actually going to inhibit that complement compliment mediated homolysis and that spilling out of hemoglobin and that's going to help to reduce the future thrombosis for MPN's though we want to shut down the bone marrow and we want to tell the bone marrow to stop producing tons of red cells and producing tons of platelets and so that's when we use something like hydroxyorhea all right now it's important to remember that when you put a patient on any kind of anti-coagulation you may need specific monitoring parameters for example if I have them on our gatra band or by Valerin I got to monitor the PTT to see if I'm within range hepin we like to monitor PTT there's actually a lot of literature that are supporting utilizing anti-XA levels or 10A levels a little bit more now because they're more accurate uh doax we we don't really usually routinely monitor these any at all which makes them attractive for long-term management but warin we need to monitor the INR and depending upon what their underlying problem is you may need to aim for two to three if they have no mechanical valve or 2.5 to 3.5 if they have a mechanical valve and sometimes with antifphos limit syndrome we actually may aim for that 2.5 to 3.5 a little bit so these are really really important things to remember now to put into perspective how these actual drugs really work things like heperin and direct thrompin and and um direct factor 10 inhibitors and and all of these drugs work we actually have to talk a little bit about the coagulation pathways you remember the intrinsic pathways you activate factor 12 then you know 11 then nine and then eight and that's going to eventually do what convert 10 into 10A and then you have your extrinsic path which is factors three and seven which are going to help to convert 10 into 10A and then 10A combines with five and that actually helps to convert prothroin into thrombin and then thrombin converts fibbrinogen into fibbrin and then fibbrin is really what helps to cross-link whenever factor 13 is present to really make a nice stable fibbrin mesh that gives you a good secondary heostatic plug so when we talk about these drugs things like for example heperin well heperin is really great because there's a couple different types that we talked about unfractionated that again that's the IV the one that we titrate very very carefully off of a PTT or low molecular weight heperin which is usually a subcutaneous injection twice daily and that one we can do more likely an anti-exa level but we really only prefer to do this if a patient has severe obesity or renal failure because those are times where it may not be cleared from the kidney as well we don't often use this one but it can be considered especially sometimes in hit funny enough is fond of parano it's a synthetic type of heperin but basically what these are doing is they're increasing anti-throman 3 levels anti-throman 3 the most potent one is it really likes to inhibit factor 10 but unfractionated heperin only can really really really suppress thromben and that's really important to remember and so if you suppress these guess what you're suppressing this whole downward cascade and you're g you're going to inhibit that secondary hemostasis this right with direct thromen inhibitors again there's IV and then there's oral the IV ones are the ones that we use in HIT right that's our gatraband and balarude and really what they're doing is they're just an alternative to heperin if the patient has hit all they do it's pretty simple they just inhibit thrombin which again inhibits this whole downward cascade and you don't get secondary hemostasis that occurs if we look at the long-term management of thrombosis again we get to the doax or warin again doax include direct thrombin inhibitors or direct factor 10 inhibitors the oral ones are usually going to be what it's debigotran and again that's really just going to do the same thing it's going to inhibit thrommen it's going to inhibit that downward cascade with direct 10A inhibitors like a pixaban river oxaban it's it's just directly inhibiting this puppy right here and again you're going to suppress this downward cascade right and if I suppress that I'm not going to get my cross fiber and I'm going to inhibit my secondary hemoasis warfrain is a beautiful one in the sense that it really acts against the vitamin K epoxide reductase which converts this oxidized vitamin K to the reduced one so there's an enzyme that helps to really process that and then we actually can go back from the reduced to the oxidized to continue the cycle with an enzyme called GGGT um so whenever you give something like that it's really important because warin is going to actually work again in this particular process where vitamin K gets goes into the oxidized to reduce form and then whenever it goes back into the oxidized form the GGT utilizes that vitamin K to convert the 2 7 9 and 10 into the functional components which if those are there they can actually cause thrombosis right when you give warin it actually inhibits the vitamin K epoxy reduct reductase that inhibits this step you get less reduced vitamin K less of it can go back to the oxidized form so you inhibit the GGGT from being able to convert these into functional 27 9 and 10 if I can't make these dang things then what's going to happen i'm not going to be able to produce thrombosis but what's important is out of all of these the one that actually decreases the quickest which is why we monitor PTINR for these patient is factor 7 because factor 7 is really a monitor of the extrinsic pathway which we use PTINR here and for intrinsic we use PTT so that explains that a little bit all right but again if you decrease all of these dude you're going to really shut down the fibbrin pathway and you're really going to inhibit cross- linked fibbrin and you're going to inhibit secondary heostasis so these are how these drugs are working so it's pretty self-explanatory how they work the only one that involves a little bit more explanation is the warfin inhibits the reduction of vitamin K and if you can't get the reduced vitamin K you can't convert it back into the oxides which is needed to make functional 7 27 9 and 10 if you can't make these you can't actually trigger this pathway at all the one that usually drops first and so it's the most likely to be monitored with the PTNR is factor 7 though all right my friends that covers hypercoagulable states i really hope that you guys enjoyed i hope you learned a lot and I hope it made sense and uh love you guys thank you guys and as always until next time [Music]