Warfarin | Mechanism of Action, Indications, Adverse Reactions, Contraindications

iein engineers in this video we're gonna talk about warfarin it's an amazing anticoagulant it's used for a lot of different reasons we'll talk about those reasons we're gonna focus on the mechanism of action right so we'll go into that a little bit in detail and how it works inside the liver cells we'll talk about what we use it for we'll talk about some of the things that you want to watch out for certain side effects adverse drug reactions and then we'll talk about and what kind of populations or individuals which do not want to give this too so it's going to get started alright guys so let's go ahead an get started here in the mechanism of action of warfarin right so it's actually a really cool like little action of this guy like the way it works it's pretty darn cool so if you guys remember the liver the liver has a Patou sites so what we're gonna do is we're gonna zoom in into a nice little cute little hepatocyte so this is going to be a pata site just to give you guys some orientation here and again that's a liver cell so what happens is when you take warfarin warfarin is actually taking per oral right so Pio you ingest it goes through your digestive tract right so it goes through your stomach it goes into the duodenum part of the small intestine right gets absorbed across the actual gut gets taken through the actual portal circulation into the liver and through that it's dropped off at the apat asite alright now once warfarin is brought into the apat aside it actually does get metabolized right we'll talk about that in just a little bit we'll talk about the cytochrome p450 oxidases enzyme a little Hey Arnold dude all right but let's talk about how it actually works now if you guys want to know a little bit here there is a specific type of structure that is really important to making clotting proteins that's what our liver does our liver makes a lot of clotting proteins and there's really important clotting proteins that are involved in this process so here's what happens you have a specific molecule called vitamin K right now vitamin K can exist in a couple different forms and the first form we're gonna talk about we're gonna say it's what's called a Quin noon so we have vitamin K in the Quin own State and what I want you to remember about this is that it's pretty much in a oxidized state what happens is vitamin K Quinton is going to be Matata it's actually reacts with a specific type of enzyme and we're gonna call that enzyme quinone reductase so we'll call this enzyme quinone reductase and how does he actually reduce this vitamin K Quinn oh that's a great question guys he uses a specific type of molecule here called in adp H and what NADPH does is he drops off hydride ions onto the vitamin K quin own and if you guys remember hydride is basically whenever you have a proton the two electrons on the hydrogen atom right and that converts this into nadp+ so you lose the actual hydride ions now from there the vitamin k quinone is converted into a reduced form here and that reduced form is called vitamin k hydroquinone so now we're gonna have vitamin K hydroquinone now the next thing that happens is this vitamin K hydroquinone is going to react in another step there's another really important enzyme right here so here's n't gonna be this cute little enzyme let's do this enzyme and orange here's this guy and this guy is called gamma glutamine carboxylase so we're gonna call this guy gamma glue to mil carboxylase okay you see a little gamma sighing cute little guy right so gamma glue to milk carboxylase guess what happens here vitamin k hydroquinone is gonna react with this gamma glue to milk carboxylase so what happens is this vitamin k hydroquinone actually drops off its electrons onto this gamma glue to milk carboxylase now when it does that it drops off its electrons right so here we're gonna say drops off these electrons cute little electrons onto this gamma glutamic carboxylase it then gets converted into another oxidized form so this is the reduced form okay so hydroquinone is the reduced form here I'm gonna put Li here on the side here this is the reduced form of the vitamin K the vitamin K Quin own and what's called vitamin K a POC side these are mainly the other forms of vitamin K which is usually this is the oxidized form okay what will happen is the vitamin K Epoque side will get converted back into the vitamin K Quin own through another specific enzyme and this is the enzyme that I really want you guys to remember here let's do this one here in this maroon H color here this enzyme is called vitamin K up oxide reductase so they call this enzyme here vitamin k Epoque side reductase now what this vitamin k Epoque side reductase does is is it helps to be able to stimulate this reaction going from vitamin k Epoque side to vitamin K Quay known and it does that by donating electrons so what happens is this vitamin K Epoque side reductase will donate electrons to the vitamin k Epoque side there's a specific type of like substrate group that's coming off of this guy if you guys really want to know it it's coming off here and it's called a Thyle group and what happens is this helps to be able to donate electrons onto the vitamin k Epoque side and convert it back into the vitamin k kwinto the gamma glutamic carboxylase enzyme is basically going to do what it's going to carboxylate these specific types of clotting proteins now what is carboxylation it's really a simple thing all you're taking is adding on a co2 molecule right so you're basically taking and you're adding on this group right here onto a specific molecule and what that's going to do is that's going to help to be able to make this molecule more functional okay these proteins are not in their functional state okay so in other words they're not really going to work unless we carboxylate them properly okay so in order for us to do that we have to add this carboxyl group on to it to make them functional proteins what are some of these clotting proteins that we need to do this two factor two factor seven factor nine factor ten protein C and protein s these guys get carboxylated and when they're carboxylated they go and get converted into a nice functional form okay so now they're gonna be converted into a functional form so you're gonna have this functional factor 2 factor 7 factor 9 factor 10 protein C and protein s and we'll just put here functional okay it doesn't mean that they're activated they get activated when we talk about that in the coagulation cascade all I want you guys to remember is without this gamma glutamic carboxylates adding this carboxyl group onto these molecules they wouldn't be properly functional they wouldn't be able to do their job whenever they are activated okay so with that being said this is the mechanism of how we synthesize and functionalize these actual clotting proteins 2 7 9 10 C and s really quickly protein C and s here's what I want you to remember about these guys these ones are what we call anticoagulants they're naturally anticoagulate 'iv right so they are naturally anti coagulants whereas these ones factor to factor 7 factor 9 and factor 10 these are more of your pro coagulants okay that's important and we'll talk about why that's important whenever we get into some of the side effects of these okay so this is what I want you to remember these want to promote clot formation these want to inhibit clot formation and there is a specific reason why we should know that I'll talk about that afterwards now you give the drug warfarin right someone is basically taking the warfarin / orally it gets absorbed across the GI tract gets taken up into the liver what does it do within this process you see this guy right here that I told you is very very important that's what warfarin is gonna be working on so now let's take this warfarin guy whoo Grady take this warfarin and look at him what is his function he is going to work by inhibiting this enzyme let's follow the process here if you inhibit the vitamin K Epoque side reductase what does that mean that means that the vitamin K Epoque side can't get converted into vitamin K kwinto if vitamin K Quinton can't get reduced into vitamin K hydroquinone then it isn't able to drop off electrons onto the gamma gluten meal carboxylase if Gambel glutamic carboxylates isn't able to add this carboxyl group on to proteins 2 7 9 10 C and s they're not going to be able to be functional so you have not properly functional Club Pro coagulants and anticoagulants now let's focus mainly on the pro coagulants in this seat what do these want to do they want to promote clot formation so if you decrease the actual production of functional procoagulant what do you lose you lose that clot formation process so now you're going to be inhibiting clot formation that should make sense let's go a little bit deeper than that now you take these proteins and you throw them out into the circulation right so we throw these proteins out into circulation if you guys remember what their involvement is in the coagulation cascade it's gonna make so much sense if you guys remember whenever the platelet plug is formed it forms these negatively charged surfaces on the platelets right and what happens is is that takes a specific protein called factor 12 and it activates him so now you have this activated form of factor 12 then what happens is factor 12 then takes and activates another factor called factor 11 then this factor 11 goes and activates another one called factor 9 and then factor 9 will then combine with another one called factor 8 and what that'll do is that'll make this specific complex that can stimulate another molecule which is called factor 10 factor 10 will then combine with factor 5 platelet factor 3 and that will convert prothrombin into thrombin brahmin is factor 2 now what happens is thrombin will then do what he'll come over and activate another factor which is actually going to be factor 1 so you take this molecule called fibrinogen which is basically the soluble protein produced by liver and you can convert that into an insoluble protein molecule called fibrin and again remember that this is factor 1 another thing that thrombin does is is he activates factor 13 and this activated factor 13 does what it basically cross-links the fibrin strands and so you get cross-linking of a fibrin mesh and that basically gives you this nice stable clot that we need right now there's another process here where you guys remember if there's damage to the tissue around the actual outside of the blood vessel where the blood is contained that can release a specific type of molecule called tissue factor and if you guys remember what happens with the tissue factor so let's say that here's going to be the tissue here right it releases this from whenever it's damaged or injured it releases what's called factor 3 and they also call this tissue factor factor 3 will then activate another specific protein and what is that protein call I'll give you a hint it's right here factor 7 let's actually highlight him a little bit here so what it does is it activates factor 7 and converts this into the active form and 7 is going to be a stimulator it's also utilized to convert factor 10 from the inactive form into the active form isn't that important that's very important so here's what I want us to do let's look and see how this is involved factor 2 where is it involved if you inhibit this if you inhibit factor 2 you inhibit the formation of fibrin if you also inhibit that you inhibit the formation of factor 13 which cross-links the fibrin mesh why is that important do you guys remember that whenever we have that fibrin mesh what it does it basically anchors down that actual there's our fibrin we're gonna cross-linked it now to anchor down that actual platelet plug on top of that we have factor 7 where's factor 7 that's a part of this little extrinsic pathway remember whenever there's damage to the layers outside of the blood vessel it releases factor 3 tissue factor that gets into the blood and then reacts with factor 7 turning it into the activated form which then stimulates factor 10 and that continues down this process to make our fibrin mesh right now factor 9 it's also involved in the intrinsic pathway factor 10 is involved in the common pathway so here's why if you can tell from this you inhibit these you inhibit a significant process of clot formation let's talk very briefly about this protein see in protein s and more specifically as protein see that we worry about reason why is protein s it's a cofactor for protein C so really the two are pretty much going to be the same function in general so how does that work go back to that hemostasis video if you guys are confused with any of this process on the endothelial lining you guys can remember there's a specific protein called thrombomodulin we talked about that in the beginning of the video what things help to keep the blood naturally thin we talked about nitric oxide prostacyclin heparin sulfate and thrombomodulin so what is this molecule here called he's called thrombomodulin now what happens is thrombomodulin will bind on to another protein called thrombin and what happens is whenever it's bound to thrombin it causes thrombin to take this protein produced by the liver called protein C which is actually bound to its with its cofactor protein s in turn protein C into its activated form will put CA there okay now what protein C does is is heat breaks down or inhibits two specific proteins that you guys got to remember so I'm gonna and that is factor v and factor 8 it will inhibit these two forms of clotting proteins why are these important what is factor 5 help with it helps to be able to activate factor 10 which helps to convert prothrombin to thrombin which basically helps to make fibrin fiber makes the fibrin mesh which helps to stab stabilize that secondary platelet plug what about factor 8 factor 8 reacts with factor 9 factor 9 then helps to activate factor 10 to factor 10a which then helps to activate thrombin which then helps to form fibrin and again you get the stabilization of the secondary platelet plug so basically what happens with this and this is where people can get a little bit confused in the beginning of once someone is taking warfarin protein C has a very short half-life so because of that the onset of whenever these this you're taking warfarin the first thing to actually be the most affected format is the protein C in protein s so remember what is it doing it's decreasing the function whenever you're taking warfarin of protein C and protein s so if you think about that if I get a decrease in the funk the production of functional or activated protein C am I going to be able to inhibit factor 5 in factor 8 no and so now these concentrations are going to go up when they go up what does that mean oh my gosh if I have an increase in factor 5 I increase factor 10 make more thrombin make more fibrin I'm going to enhance that platelet plug Zack how does that make sense what about factor 8 factor 8 oh it's gonna react with more factor 9 activate factor 10 make more thrombin make more fibrin and then stabilize the clot exactly I thought you said the warfarin is an anticoagulant it is but whenever you first take warfarin it has this ability to cause hyper coagulation within the first couple days of taking it and that's one of the things that we have to understand why it's because protein C is the first thing to get affected protein C and protein s are the first clotting factors to be affected within the first few days of taking warfarin what does that mean that means that there hypercoagulable because they produce a little bit extra activated factor v and activated factor 8 which helps to accelerate clotting process after a couple days though the effect on protein C in protein S is overtaken by the factor 2 7 9 10 these guys their concentration starts decreasing if you decrease the concentration of factor 2 you decrease thrombin you decrease vibrant production and you decrease this clot if you decrease factor 7 you decrease the activation of 10 thrombin in the fibrin if you decrease factor 9 you decrease the activation again of thrombin and fibrin mesh and again factor 10 you decrease the activation of thrombin you get the point then eventually you're gonna have this anticoagulant effect so remember whenever you first take warfarin first couple days you're hypercoagulable why because protein c is the first one to be affected after a couple days goes on protein c and protein hypercoagulability will be overtaken by the decrease in functional protein factor to seven nine and ten which will cause the extract by inhibiting these specific proteins all right so the last thing that we need to understand when we're talking about warfarin especially with the mechanism of action because it goes hand-in-hand is potential drug interactions whenever you're putting someone on warfarin whether it be for afib whether it be for prophylaxis against like a DVT or PE or after they've had a surgery or they have heart failure whatever it is you want to make sure that you're looking to see if the patient is on any other medication that could either increase the concentration of warfarin make them bleed or decrease the concentration of warfarin basically they still clot that is important so how do we how do we do that look in their history and figure out oh is this medication gonna be a potential one how do I remember all the medications I got you guys it's gonna be a good quick little mnemonic device that I like to remember particularly as those that actually increase the effect of warfarin so how do you remember that so I remember oh devices and this isn't all of them but this is the more common drugs that people are on that can actually particularly do what to this enzyme well let's think about it warfarin is actually going to be broken down by the specific cute little Hey Arnold enzyme what is this enzyme called this enzyme is called the cytochrome p450 oxidase and what happens is warfarin is actually broken down and metabolized by this enzyme so you're gonna get the metabolites that can then be excreted right but we need to know if we inhibit this enzyme we inhibit the breakdown of warfarin and increase the concentration of warfarin so this is going to be the drugs that are going to be particularly inhibiting this enzyme if you inhibit this enzyme you have less breakdown of war what are some of these drugs a map Brazil which is a proton pump inhibitor right so it's good for people with a GERD maybe peptic ulcer disease dice all freedom this is actually a medications if you give to patients who are alcohol abusers and want to undergo the withdrawal process basically they want to stop drinking it's a prophylactic medication because if you drink alcohol and take this medication it causes you to get really sick you get nauseous you will be you you vomit you feel terrible ethanol particularly acute use of a Cathan all so AK you use of ethanol can also affect warfarin without pro ik acid or valproate this is an antiepileptic use it for migraines you can use it for bipolar disease a lot of different things isoniazid which is also abbreviated as inh it's an anti tuberculosis medication see ciprofloxacin which is a type of antibiotic there's another medication called cimetidine they use this a lot in anti histamine medications another thing is erythromycin not as commonly used by as compared to its brother as a thorough Meissen but it is a type of macrolide that can be used to treat a multitude of different types of bacterial infections and the last thing is going to be soulful drugs again these are going to increase warfarin or for rent okay because they inhibit this enzyme which basically inhibits the breakdown of warfarin into its metabolites the other one that I want you to remember is CP bars yo so CP bars so CP bars is going to be the name of the drugs that are going to stimulate this enzyme if you stimulate this enzyme you increase the breakdown of warfarin into its tomato petabyte therefore decreasing the warfarin concentration so you want to remember SI p bars and again these are some of the big ones so one of them is called carbamazepine okay they use this in patients with trigeminal neuralgia they can use it as an antiepileptic they can use this for patients who are also struggling with bipolar disease right another one is called phenytoin it's an antiepileptic medication barbituates this is gonna be things like phenobarbital okay another very powerful sedative antiepileptic medications that can be used in like status epilepticus alcohol particularly chronic alcohol use so chronic alcohol use so you got to watch out for what else rifampin which is another type of anti tuberculosis medication and st. John's wort okay so these are important drugs that you want to watch out for also think about it what is involved in the warfarin process the mechanism of action vitamin K you got to be monitoring their vitamin K levels as well in other words you know being careful so we have to also monitor so monitor their vitamin K intake or levels and how do you do that again go into their history what if they have a disease that decreases their vitamin K absorption in other words they're like silly act disease right where they don't absorb it a lot because there's damage to the small intestine through certain types of autoimmune mechanisms or what if they have pancreatitis chronic pancreatitis where they don't produce those pancreatic enzymes to break down those nutrients that you can absorb them you don't get vitamin K what if they've been on antibiotics very powerful antibiotics that destroy their bacterial flora that in our bacterial flora do two nice things for us they give us complex vitamins like B vitamins and vitamin K so if you decrease the vitamin K levels for whatever reason what is gonna happen to this process well less vitamin K is actually going to be what think about it vitamin K is needed if less vitamin K is here then that's less vitamin K époque Saida reductase that is actually going to there's going to be more of this vitamin K of hoxa2 reductase to inhibit the low vitamin K levels so if you have low vitamin K you're gonna have more inhibition of these Pro coagulants and therefore you're going to bleed more likely so you have to be careful if someone has low vitamin K they could have more increased risk of bleeding okay so watch out for that all right that covers our mechanism of action of this drug let's go into the indications all right guys let's talk about the indications of warfarin it's very good at being able to and hit inhibit clot formation so it's good for preventing thromboembolism z' so with that being said what do we use it for well as you can see here we had a leg with a vein in it it's a deep vein and then we got our lungs which are going to be very nicely connected to that right so one of the good reason one of the big reasons that we use this is actually prophylactically warfarin is you take it / orally and it actually takes a little bit for it to actually start to kick in takes a couple days so it might take somewhere up upwards of you know two to three days before it actually starts experiencing the maximum effect because it has a half-life of about 40 hours so it might take about two or three days before it really starts to kick in and become unable to do its job that's not good whenever you start when someone is having an acute pulmonary embolism so that's not really the drug that we give whenever someone is having an acute PE or an acute DVT we're more likely to use drugs like heparin and we'll talk about that in another video but if someone is basically had hep to treat their acute DVT and PE and they need prophylactic treatment for developing one in the future then that would be a good job for warfarin because that's gonna be more of a chronic prophylaxis management right so if someone has had a previous DVT so it's good for prophylactic so good for prophylaxis of DVT and PE because we know that whenever someone develops clots with inside of this deep deep veins of the calf what happens it can travel up through the inferior vena cava into the right atrium from the right atrium it gets pumped out into the pulmonary circulation and that embolus can then block blood flow to the lungs and that can lead to very dangerous symptoms obviously to kipnis shortness of breath maybe hemoptysis maybe they have some chest pain okay from there what do we do if someone we think someone's having a PE you obviously gold standard especially if they have a high degree of suspicion is go to send them to get a CT angiogram right so they do a helical CT scan look to see if there is any types of clots or filling defects within the pulmonary circulation okay but again you're gonna treat them acutely with wet with a heparin and then long term chronic prophylaxis if they need it you're give them warfarin prophylactically okay so that is another option what's another thing that you got to think about what if someone has had some type of surgery not just that they recover from a PE but they had some type of severe surgery which caused them to be bedridden all right so remember this is why it's so important if someone's bedridden and they're not able to move around what is that effect FERC owes triad remember that from physiology FERC owes triad says that if someone has stasis if someone is hyper coagula bull if someone has endothelial dysfunction or injury what does this do this increases the risk of thrombosis right and that's Vercoe triad so if someone is recovering from a PE or DVT and you want long-term prophylaxis against them developing another one you can give them warfarin or if you want prophylaxis of a DVT or PE after someone is recovering from a surgery that's causing them to be bedridden such as a total hip replacement total knee replacement some type of hip fracture surgery anything that's causing them to be bedridden it's good to give them warfarin for those reasons okay that is something that you want to know all right sweet deal the other thing that you see warfarin using a lot in it is because it's a very common condition is atrial fibrillation why is this important because afib is an arrhythmia right we talked about this a little bit in the EKG series it's an arrhythmia that develops reentrant circuits or multiple ectopic focus basically fire off at all different times and rates and basically the atria don't properly contract go back to berkos triad if the atria is basically not able to properly contract it's like quivery what happens to the amount of blood that's being pushed from the left atrium into the left ventricle it's decreasing because the contraction the power of contraction pushing the blood from the atria to the ventricles it's decreased so blood starts to kind of pull up and accumulate in the atria it stagnates what happens whenever there's stagnation of blood clots and then because of that you can develop these thrombi on the valves okay there's multiple different reasons why patients can develop a fib we're not going to go into that I just want you to know that if someone does have afib why are they more prone to clots it's because the HRE are trying to contract right push blood into the ventricles if they don't contract as well because they have multiple different sites trying to fire at the same time because of that it's not going to properly develop enough force to push all the blood that it needs to from the atria to the ventricles and some of the blood is gonna sit inside of the atria if blood doesn't move what happens you can lead to stasis which leads to thrombosis and they can develop on these valves why is that a problem let's say for whatever reason you go through some acute stressful like event and because of that that thrombi breaks off where can it go oh it can go to a lot of places if it goes and breaks off here can go up into the coronary circulation and cause an MI it can go into the aorta go down and actually go up through the carotid system and affect the brain what can that cause oh that could lead to an ischemic stroke okay and we don't want that so that could lead to an ischemic stroke all right a CVA so we don't want that to happen what else could happen a clot could then go and travel not just into the actual carotid circulation into the coronary circulation but it could also go into the intestines and it could block the blood flow going to the intestines what can this cause this can cause something called especially if it's the SMA if it's a super a mesenteric artery it can cause mesenteric ischemia and if it's affecting more of the IMA then it can cause what's called a schema colitis okay and that's just because of their blood flow so IMA is more likely to be ischemic colitis and SMA is more likely to cause mesenteric ischemia other places if you really want to know because I know you guys do it you also got to be careful for the kidneys okay so also watch out because it can affect the kidneys and it can cause renal insufficiency okay so watch out for the kidneys and another one that you have to watch out for is the spleen those are common areas where these infox can actually these thromboembolic and form so big ones that you want to watch out for watch out for the blood supply that's going to the myocardium itself so imagine here this is going to be the we re here right you got to watch out for thrombi going to the coronary arteries okay this is a nimble I that can break off from that valve travel into the coronary circulation causing mi the blood can actually go into the kidney right you can actually form an embolus that forms within the one of the renal vessels into the carotid circulation into the mesenteric circulation even going to the splenic artery to the spleen okay these are things that you got to be careful of so if someone has a fib whether it be valvular or non valvular atrial fibrillation that's one reason that we should give them warfarin what's another one what's another thing that could actually cause blood to stagnate in the ventricles what if someone had a significant myocardial infarction so they had a significant mild cardial infarction and all of this area of tissue is replaced by fibrous tissue can fibrous tissue contract know if fibrous tissue can't contract what's going to happen to the area of blood that can pull up in this little area right here it can form a thrombi so you can actually get a left ventricular thrombus as a potential complication of someone having a very significant MI so we have to watch out for that as well so if someone had a recent myocardial infarction they can get a left ventricular thrombus also what if the ventricles aren't pumping enough what if their strength they're not pumping enough blood out and a lot of blood is staying within the ventricles what could happy do to CHF so anything that can basically cause a stagnation of blood within the atria or the ventricles could be potential reasons of someone developing a thromboembolism ink and getting transferred to the brain so the myocardium to the intestines to the kidneys maybe even the spleen okay so watch out for a fib watch out for post mi which can basically lead to a left ventricular thrombus and also watch out for CHF okay because they develop a decrease in the contractility you may if they have a decrease in the contractility you guys will also remember that they're going to have a decrease in the amount of blood that's actually being ejected out right so we have a decrease in their stroke volume but because they also have a lot of blood remaining in there the amount of blood that remains in after ventricular contraction right your ESV that's actually going to increase so they're gonna have a lot of blood sitting in two ventricles afterwards and again that promotes a lot of stasis and therefore clots that is what you got to be careful of with these okay so warfarin is designed to be able to have it that now last thing we gotta talk about the indications here is how this little bit about this pt/inr thing how do we do this I just want to briefly go over it remember I told you that pt/inr is a way that we monitor the extrinsic pathway okay so how does this work you take a test tube okay here's gonna be a test tube and what we do is we draw some blood from the patient when we draw the blood from the patient we're going to separate it and we're only going to take the patient's plasma that's all we want right now we just want their plasma so we're gonna take and separate it out and get just the patient's plasma okay so we'll centrifuge it we'll take some of this stuff off the we'll take that plasma off the top of the test tube transfer it into another container then what we'll do is we'll send it to a lab different labs have different types of kits and all of those different kits have different control times in other words if you take a population in Wisconsin you take a population in Pennsylvania you take a population in Connecticut wherever there's different PT's okay control PT's based upon the kit that you use so what would they do is in the lab they'll take the person's plasma and they'll give them what's called tissue factor you guys remember that tissue factor of factor 3 they'll add that in and then once they add that in they're gonna measure the time it takes for this to undergo clot formation so they'll add that in and they look to see when does it actually form a clot so we're gonna sketch out a different color here it's gonna be all clotted up now okay this right here this time is called the PT but we need the problem is is that pts we need a some type of like standard - like a standard ratio that we can compare it to okay so now let's take for example the time that it takes for this blood to clot let's say this is my blood all right and so we say okay let's say exacts PT all right and that is what does Pt stand for let's just actually write that over here this is pro thrombin time that's what it stands for right so we're gonna take my PT and let's say that it's 23 seconds okay so that's gonna be the time it takes for my blood to clot okay then we're gonna say let's take a kit we're gonna just call this kit a okay and kit a every kit no matter what lab has a control PT and let's say that that control PT happens to be I don't know 11 seconds what we need to do is get a ratio between my PT and that labs PT so what I'm gonna do is I'm gonna divide these two so now if we take this into consideration I want to know what's the ratio between these so that's called my INR my International normalized ratio so 23 divided by 11 it's going to be around it's gonna be around like - okay so that's like two point do you know oh nine all right so because of that that gives me a decent-sized number now normal pts for patients who are not on warfarin is usually like less than or equal to about one so we can say normal PT so if we're saying a normal PT is usually somewhere around less than or equal to one okay when someone is on warfarin we don't want that we want it to be a little bit higher okay so we want it to actually be between two and three okay so what we want for a person who is taking warfarin we ideally want their INR so while on warfarin we want the patient's INR to be a little bit higher than one we want it to be somewhere between two to three okay that's kind of right around that sweet spot there is another time where if someone has a heart valve because heart valves can be thrombogenic like a prosthetic heart valve you do want it to be just a little bit higher you can go maybe up to four max some books will even say 3.5 so you if they do have a prosthetic heart valve you might want to be a little bit higher because prosthetic heart valves are highly thrombogenic depending upon what type you get but either way that's what I want you guys to understand about this so it's super simple you give too much warfarin what's gonna happen if you give too much warfarin you're going to inhibit the extrinsic pathway very very strongly right and again we're talking mainly about factor seven it's the most effect on that you inhibit factor seven you don't clot so the time it takes before this blood to clot is going to increase that means that this number will climb and climb and climb so sorry I take too much warfarin that might climb to like 38 seconds 38 seconds divided by 11 seconds oh my gosh that INR is gonna go really really high so a high INR means that they're giving too much warfarin it's a simple concept all right so high INR means too much warfarin what if I have not enough warfarin that means that that factor seven can still form clots and it might be a little bit quicker than usual so now my PT is going to decrease maybe it goes down to 11 seconds wasn't my iron are now 11/11 is one so now my PT drops so what I want you to remember low INR means you're more likely to form clots in the K this case the warfarin particularly considering this is what the peuta cringe we won it in if you go above that higher than three again your high at risk of bleeding okay so that's why we have to take into consideration their dosage as well as what medications and foods they're consuming okay so that covers the indications and also about the pt/inr monitoring okay so last thing that I wants to talk about here is their adverse drug reactions and contraindications it really is simple that we need when you think about it when someone's taking warfarin it's an anticoagulant so if it's a blood thinner right so there are more at risk of bleeding especially if you take too much of the warfarin or you have another drug that you're taking that can increase the concentration of it like we talked about oh devices right or you have very little of that vitamin K right again these are things to take into consideration so what are the risks bleeding what kind of bleeding it's really simple you just got to look at some of the things like for example they could have some gingival bleeding right they could have some anterior epistaxis look at our little French dude that we got here you could be bleeding alright so epistaxis all right what about blood coming from another orifice what if it's coming from the actual rectum right so you have blood coming out from the rectum this could be things like Melina especially if it's dark blood right that means that it's an upper GI bleed more likely or it could be hematochezia right so it could be some bright red blood or they could be vomiting up blood right so there could be some hematemesis and depending upon the color of that that could also be important to take into consideration you also think about other things what if it's just like you know from the skin you get petechiae you get prepared you get a combo --ss all those easy bleeding signs maybe have blood in the urine maybe that's not even the thing maybe you don't even find the bleed and the patient is actually fairly fatigued they're hypotensive they're tachycardic and you do a hemoccult right so you take and you do a digital rectal exam you do the hemoccult test and it comes up positive these are all things that you have to think about whenever you're putting someone on warfarin it's also really important before you put them on warfarin make sure that you check their CBC check that CBC check their actual coag's beforehand before putting it on it and then monitor it as well one of the really weird things with with warfarin is it can cause murmur I told you that within the first couple days of taking warfarin it actually decreases protein C and protein S which can cause hypercoagulability remember I told you that so we said that whenever you take warfarin right so warfarin we're gonna say within the first let's say two to three days of taking it it significantly inhibits protein C and protein s why is that important protein c and protein s what do they normally do they are normally designed to be able to inhibit factor 5 and factor 8 and what do these naturally want to do they want to stimulate thrombus formation okay so if you give warfarin two to three days first hint it inhibits protein C and protein s pretty strongly in the first couple days because these have very short half-lives and their first affected so now their concentration significantly decreases if the protein c and protein s concentration significantly decreases what happens to the ability to inhibit factor v and factor 8a that decreases so now instead of actually inhibiting them you're going to actually allow for them to have a loss of inhibition so now there's a stimulation to the production of us to the activation of factor v and factor 8 and that increases thrombus formation and because of that think about that if you form a thrombus within the vessels small vessels around this of the skin what happens to the blood flow going to this area that's going to have a decreased blood flow decrease blood flow decrease blood flow what do you get as a result of that that ischemia leads to necrosis and the tissue starts to die and then you start getting this actual necrotic tissue so again what's gonna happen you're gonna get a decreased blood flow because of these thrombi and you're gonna start seeing necrotic tissue formation what areas do we worry about this necrosis occurring in we worry about area such as this is called wool specifically we worry about like the limbs that's one area the breasts the penis okay these are areas that are commonly affected whenever someone is taking warfarin and it can cause necrosis of that tissue area what do we call this we call this let's give a different color let's call this warfarin-induced skin necrosis warfarin-induced skin necrosis this is something that you have to watch out for when you're putting someone on warfarin okay now how do we prevent this it's actually a very simple thing to prevent this because your hypercoagulable within the first couple days of taking it guess what you do you put someone on heparin so you give them heparin and what heparin is going to do is heparin is actually going to work by inhibiting thrombin and factor 10 so what it does is inhibits factor 10 and it also inhibits factor 2 so factor 2 which is actually going to be thrombin we'll just put that here it inhibits these guys and basically by inhibiting that you inhibit thrombus formation right so you give heparin in the first couple days of taking warfarin because I don't inhibit factor 10 to factor two which one hibbett thrombus formation so we call this bridging therapy so whenever someone is going to be taking warfarin with the first couple days you give them warfarin and you give them heparin because heparin is going to basically counteract to this thrombotic effect after that warfarin starts to kick in then that antha the procoagulant properties those are going to be inhibited and again you're gonna lose this hypercoagulability so again always bridge with heparin for the first couple days of starting warfarin another thing you have to remember is if someone is really bleeding like you give them too much warfarin for whatever reason or again there's a some type of drug that they're taking and it's increasing the concentration of warfarin really really crazy what's there at risk for their risk for bleeding what's the first thing you do patient comes into the emergency department they're bleeding they have history of afib their records show that they're taking warfarin you get blood work okay when you get the blood work you find that their PT is super elevated you find out that their INR is super elevated what are you worried about they might have too much warfarin and they're bleeding you need to give them an antidote something that's going to prevent this from continuously developing this this bleeding process so what do you treat them with when the patient has too much warfarin you need to remember the antidote for this situation first thing you do is you start them on a slow infusion of vitamin K okay so you give a slow infusion of vitamin K usually like 5 to 10 milligrams you start them on the slow infusion of vitamin K takes a couple hours before it really kicks in the next thing you do is you give them a combination of something else so there's two options research has shown that between these two one is a little bit more superior they say that the prothrombin complex concentrate is more superior than the fresh frozen plasma okay but the main thing is that you give them one of these two agents all this PCC is is this just a complex of factor 2 factor 7 factor 9 5 factor 10 okay factor 9 and factor 10 and they throw in some other stuff in there like protein C protein s antithrombin 3 to have some of that kind of counter active effect fresh frozen plasma is all the clotting proteins all clotting proteins okay this is just a little bit quicker the pcc is a little bit quicker into the system it's going to provide a little bit more effect it is a little bit more expensive though but it's more superior to the fresh frozen plasma when someone is having an acute bleed due to excessive high amounts of warfarin levels that they're taking too much for whatever reason first thing you need to remember if they are give them vitamin K and give them PCC prothrombin complex concentrate or fresh frozen plasma it really depends on preference they say that the pcc is a little bit more superior and what's that going to do think about it you're giving these quite these pro coagulants what's it gonna do it's gonna basically help to allow for some clotting right so you're gonna allow for some clotting fresh frozen plasma again you're giving all the clotting proteins if you give vitamin k what is that going to do that's going to over saturate the vitamin k Epoque side reductase if you over saturate it what's it going to happen then you're still not going to be able you're not going to be able to inhibit on the production of those pro coagulants and so those pro coagulants will still so this is important to remember whenever someone is bleeding a lot give them vitamin K and PCC or fresh frozen plasma alright guys so last thing that we need to know but before anything this video with a warfarin is what are some contraindications things that you got to watch out for it's really simple understanding a lot of the stuff that we talked about already it should really make sense what structure inside of the body makes clotting proteins liver alright so if someone has let's say liver failure okay their ability to produce clotting proteins so clotting proteins what's gonna happen there's gonna be a decrease in the production of clotting proteins so if you give them warfarin what could happen well they don't make very much clotting proteins as it is you give them warfarin you're gonna significantly decrease the number of coagulating proteins so what can happen they can seriously bleed so that's something that you have to think about if you have decreased clotting proteins what's warfarin going to do warfarin is basically trying to inhibit the production of clotting proteins so now you're gonna have less clotting proteins within the blood that's going to make it extremely thin within the blood again anticoagulant like effect and they're at a higher risk of bleeding simple thing okay so liver failure you can give it if you want to try to but you really need to be so careful in these patients because again they're at high risk of bleeding all right next thing pregnancy you do not give warfarin to pregnant women it's teratogenic it can produce a lot of different congenital defects what are some of the congenital defects to mention the main thing that you want to remember is it can affect the little baby's heart right so it can cause congenital heart defects so it can cause congenital heart defects if you really want to remember one is called patent ductus arteriosus and the other one is called coarctation of the aorta and that's really sad you know so these are conditions that are you know definitely can affect the quality of life right another thing that's even more severe than that is it can cause central nervous system malformations okay so it can cause changes to what's called you know guys notice their corpus callosum it's the structure that collage communication between the right and left hemisphere that can actually decrease in size okay they can have a smaller head they can have fluid that builds up with inside of the actual subarachnoid space so this can cause a lot of central nervous system dysfunction okay and last thing is it can also affect the facial structures so another thing is it can actually affect like the nose it can affect the specifically the airway and what happens it makes the nose really really tiny and it makes the nasal cavity in the back of the nasal cavity super super tiny it's called colon ol atresia it causes thickening of the larynx it caused laryngomalacia to get a cleft palate all of these things basically alter the actual flow of air and this can lead to respiratory distress okay so these are things that you want to be careful of again contraindicated in pregnancy because it can cause central nervous system dysfunction leading to mental retardation respiratory distress through structures changes within the face and congenital heart defects that can definitely alter the quality of life within a child last thing it really is simple bleeding risks if someone is actively bleeding are you gonna want to give them some type of medication like warfarin if they have uncontrollable hypertension which can lead to an aortic dissection right so things like what could it be a risk for bleeding risk again simple if they're actively bleeding if they have risks that can cause very dangerous things if they have high blood pressure uncontrollable high blood pressure the reason why is that could lead to an aortic dissection what if they have an aortic aneurysm okay so they have an aortic aneurysm and then again you give them an anticoagulant somehow it ruptures because it's greater than five point five centimeters again they're gonna bleed there's a lot of different things that we have to be careful of but you just got to be again attentive to the fact of are they having anything they could increase the risk of them bleeding what are those things and does does the you know the risk outweigh the benefit in this situation it's better to err on the side of caution and watch out for this stuff and maybe find another medication instead okay so that gives us everything we need to know about warfarin [Music] and we should know that that is really important oh my gosh