DIP Episode 8 - Comprehensive Heme Pharmacology

Hello, welcome. My name is Divine. I am a fourth-year medical student. Welcome to an eighth episode of the Divine Intervention Podcasts. Today we're going to be talking about him from ecology. I basically will try to cover every high you thing you need to know relating to him from ecology in this podcast. Okay, so let's go ahead and get started. And first to start, I think it probably makes sense to discuss the primary coagulation cascade. Okay, so let's assume you get a nick in the skin, right? You disrupt college, you disrupt your endothelial cells. That will enable you to express the collagen below those endothelial cells, called the subendothelial collagen because it's below endothelial cells. Okay, and when you expose that subendothelial collagen, the next thing that happens is you expose vanwili-brand factor. And remember that vanwili-brand factor is found in two spots, right? You can find it in the wide-bow paladi bodies of endothelial cells and also in the alpha granules of platelets. Okay, so that vanwili-brand factor basically serves as a go between between subendothelial collagen and GP1 B9. GP1 B9 is a receptor found on the surface of platelets. This is the adhesion step of primary hemostasis. Okay, and remember if you have a deficiency in GP1 B9, that's a Bernatulese disease, right? Basically here your PT and PT2 will be normal because there's nothing happening with your clotting factors and your platelet count will actually be normal.

Okay, although classically it's low in Bernatulese disease, but your bleeding time should certainly be increased. And the restocity and co-factor acid should be abnormal, right? Because anything that impairs the adhesion step of primary hemostasis is associated with an abnormal restocity and co-factor acid. Okay, so if talked about the adhesion step next step is activation. And basically the thing that happens here is that platelets release ADP from the adense granules and that ADP binds to the ADP receptor. Okay, that receptor is a GI-computer receptor. So you should already know that it's job will be to inhibit adenylide cyclase. If you inhibit adenylide cyclase, you have less conversion of ATP to cyclic AMP. Okay, and in this activation step you also release thromboxin E2. Okay, so again, moth thromboxin E2 release less cyclic AMP. Okay, this whole process triggers the expression of GP2 B3 receptors, which heralds the beginning of the aggregation step of primary hemostasis. Okay, and just one quick off-shoe factor here is that the cyclic AMP that exists in platelets is broken down by phosphodistory three, right? So PD3 helps you convert cyclic AMP to AMP. Okay, so if we know that the adp receptor also called the P2 Y2 over-sector works by a GI coport mechanism to decrease cyclic AMP, right? We can build a construct that says that low cyclic AMP makes platelets activated.

Okay, but if cyclic AMP levels are high, platelets will not be activated and you potentially exert an anti-plitlet effect. Okay, so PD3, we said it converts cyclic AMP to AMP. If you inhibit PD3, you have increased levels of cyclic AMP, so you have decreased platelet activity. Okay, now in the aggregation step of primary hemostasis, basically, GP2 B3, the GP2 B3 receptor pairs up with another GP2 B3 receptor on another platelet. The thing that marries those two things together is fibrenogen. Okay, remember fibrenogen is factor one. Okay, as you've seen secondary hemostasis will convert factor one to factor one A. Factor one is fibrenogen, the zymogen form. Okay, and you should also please remember that deficiency in GP2 B3 A is the pathophysiology of a glansmone thrombostinia. Okay, and if you also meet or want to, but it's against GP2 B3 A, that'll be ITP, immune thrombocytopenic pupper. Okay, so basically these people they consume the platelets, so they lose the ability to form clots and the classically presents with bleeding. Okay, classically presents with bleeding. And just as another aside, remember that after the vulnerable factor does its job, right? It's broken down by a protein known as Adamstis 13. Another name for that protein is vulnerable factor metalloprotees. Okay, in TTP, right, which sounds eerily similar to ITP, okay, you have a deficiency in Adamstis 13, right? So you cannot cleave vulnerable factor.

If you can cleave vulnerable factor, you essentially constitutively activate cli-clots and you have an increased risk of thrombosis. Okay, and then another closely related disorder is HIT, right? So heparin induced thrombocytopenia. In this case, again, you get thrombocytopenia, but you also have an increased risk of thrombosis. So let's just look at these things real quick. So in ITP, in TTP, and in HIT, you get thrombocytopenia in all three, but in ITP, you have an increased risk of bleeding. In TTP and in HIT, you have an increased risk of thrombosis. Okay, now another cascade I want to discuss is basically the cascade that involves the synthesis of prostaglandids. Okay, so basically the thing that happens is your membrane phospholipids, they are converted to a racidonic acid. Okay, the enzyme that does that reaction is phospholipidsate to remember that phospholipidsate to is inhibited by glucocorticoids. Okay, now from a racidonic acid, you can either go down the leukotrain pathway by using the enzyme 5-lipoxygenase or the prostaglandin pathway by using the enzyme cycloxygenase, one and two. Okay, so cox-one and cox-two help you convert a racidonic acid to prostaglandins and it so happens that prostaglandins can be converted to thromboxin-2 by an enzyme known as thromboxin synthase. Okay, but again, 5-lipoxygenase helps us convert a racidonic acid to leukotrain. Okay, now there are some key differences between cox-one and cox-two. Cox-one is constitutively expressed.

Okay, but cox-two is an inducible enzyme. Okay, and cox-one, you find it a lot in the GI mucosa, because remember, you need to make prostaglandins, prostaglandins, work through GI coupled receptors on the surface of parietal cells to decrease the synthesis of cyclic AMP, which ultimately inhibits the activity of the hydrogen potassium ATP pump. Okay, now you'll find on the surface of parietal cells. Okay, so cox-one and heavily expressed in the GI mucosa helps you mix prostaglandins that decrease the synthesis secretion to protect the stomach lining. Okay, so cox-one constitutively expressed cox-two is inducible. Okay, so if you inhibit that cox-one, right, by giving a drug like aspirin, for example, you increase a presence risk of peptic ulcer disease. Okay, because you're removing that protective prostaglandin effect. For the 5-lipoxygenase pathway, right, we said that that helps you go from a racidonic acid to leukotrain. I remember you can inhibit that enzyme with xylutone. Okay, we'll talk about xylutone in the pump from a collagey podcast, but xylutone basically is a 5-lipoxygenase inhibitor. Although it's not used very commonly because it explodes your liver. Okay, alternatively you could also get an anti-lucotrain effect by blocking the leukotrain receptor, right, it's called CIS-LT1. Okay, we drugs like Monte-Lucast and the phyllo-Cast. So now that we've talked about these different caskies, let's talk about the anti-plethe drugs.

Okay, basically the big side effect with all these drugs is bleeding. Okay, so let's start with aspirin. It's the simpler drug. Okay, so aspirin, the weight works is it irreversibly inhibits cox-one and two. Okay, a few higher things you need to know about aspirin. First thing is it has zero-order metabolism. Okay, remember there are other things that have zero-order metabolism like phenetoin and ethanol. Okay, and the nice one you learn while you're studying for step one is phenetoin, ethanol, aspirin, algolite, like PEA, okay, and a P looks like a circle which looks like a zero. Okay, zero-order kinetics. So that means that basically you lose a fixed amount of the basically or whatever mechanism is helping you eliminate these drugs, eliminates a fixed amount per unit of time. Right, so it's like, oh, you lose 5 milligrams per hour. Okay, you don't lose a fixed percentage. Very high you to know that you lose a fixed amount per hour. Okay, so aspirin decreases the synthesis of thromboxin E2. Okay, by inhibiting cox-one and cox-2 irreversibly. Okay, because if you inhibit cox-one and 2 irreversibly, you make less per-staglandins. So you're making less fixed stock for thromboxin synthase to help you make thromboxin E2. And remember that thromboxin E2 is a potent activator of pleated activation and aggregation. Okay, and as an aside, don't forget that you can give me some prostone to a person to perfect the GMI COSA in a person that has to take aspirin chronically.

So let's say for example, they have like osteoarthritis or they have like some kind of thromb, like bad vessel disease like carotid arrestinosis where they have to chronically take aspirin. You can give those people misoprostol to perfect their, to protect the GMI COSA because you are basically bypassing the inhibition of cox-one and 2 that you get with administration of aspirin. And if they describe a kid that has brain and liver problems, right? So classically, the liver problem is hypoglycemia and they tell you that the child is in a coma and is somnolent. And this child recently had like a febrile viral or respiratory infection or got like some kind of vaccine like the vis-v vaccine or whatever. And they have all these symptoms and they took aspirin for their fever. Think about rice syndrome. Okay, very classic association. You want to know. People don't really know the pathophysiology but they think it involves some stuff that has to do with mitochondrial dysfunction. That's like a buzzword you want to remember. Now, the only time you really should be given aspirin to a kid is if the kid has caraccharis disease. Okay. Now, another high-yield thing with aspirin is something called aspirin exacerbate respiratory disease. That's like the new term. Back in the day, I believe it was called aspirin induced asthma. So what's the pathophysiology of this disorder? The pathophysiology here is that if you give a spring, you inhibit Cox-1 and 2, right?

We said that a rachidonic acid can take one of two pathways. It can take the cycloxygenis pathway or it can take the lipoxygenis pathway. So if you inhibit the cycloxygenis pathway, you increase the flux of substrates through the lipoxygenis pathway. And we know that Lyoko trains when they act on the receptors, right? So C-C-L-T-1 for example, because bronchoconstriction, right? So that can trigger asthmatic symptoms. That's why this is known as aspirin exacerbated respiratory disease. Okay. And classically, this disorder on exams presents with nasal polyps, although you should also keep other high-yield things on your differential. If you mention nasal polyposis on your exam, so you want to keep things like weglers on your differential, remember it's C-Amp positive. You want to think about cystic fibrosis as well. Okay. Now, if a person overdozes on aspirin, what happens? The first thing that happens is they get a respiratory alkalosis, okay? Because remember, aspirin can go to the respiratory centers in the medulla and activate them, so it causes you to hyperventilite. But in addition to that, you also get a high anion gap metabolic acid doses, okay? Because if you go back to your biochemistry, hopefully remember that aspirin is an uncopply agent of the electron-transport chain, okay? So if you uncoppled that, you're like, we don't see any ATP from all my efforts.

So you basically operate like colasis, and remember that lactic acid is a byproduct of like colasis, so that can create a high anion gap metabolic acid doses, okay? And remember that aspirin is also an acid, a cyto-salacetic acid, so again, that should technically decrease the pH of your blood, okay? Now, last thing I'll say about aspirin is you want to know what aspirin does at different doses, right? So, low dose aspirin, that's usually like less than 300 mix, okay? 300 milligrams, has more of an antipletal effect, but high dose aspirin from like 2400 to like 4000 milligrams, has more of an anti-inflammatory effect, okay? And then the next antipletal drug I'll discuss, so we've talked about aspirin. There, we said that aspirin is an irreversible, coxone and twin-hybridler, drugs like etyrolac and dichrofenac are reversible, coxone and twin-hybridlers, okay? So these drugs should theoretically increase KM, right? So decrease the affinity, but it should make no changes to V-mat, contrast that with aspirin, okay? Now, next drug, a celacoxid, um, celacoxid is a reversible coxone inhibitor, okay? It does not inhibit coxone, it just inhibits coxone and remember, I already said that coxone is inducible, right? So it's induced in states of inflammation. Um, so if you're taking a drug that selectively inhibits coxone, we say that all coxone is only induced in states of inflammation. You can see that you're basically living coxone alone, so you don't get the GI problems, right?

Like peptic ulcer disease, that you get with something that also clubbers coxone, like aspirin or the other drugs like etyrolac and dichrofenac. So these drugs are great drugs, they can give you the same aspirin effect you want, but you don't have any problems in your GI tract. Only problem is it so happens, at least there's some literature that says that coxone is heavily expressed in coronary vasculature and that should sort of make some teleological sense, right? Because if you think about it, if you're heavily expressing coxone coronary vasculature, you're making more prostaglandins, remember prostaglandins and viso-dialectry, so that could potentially widen your coronary vasculature and make blood flow most move fluid, so if you inhibit coxone, which is heavily expressed in coronary vasculature, you could potentially decrease prostaglandins synthesis, you could potentially cause coronary adrivisal construction, and that person will have an increased risk of a myocardial infarction. In fact, that's why some of these coxips, right? So the coxone inhibitors, that's why a lot of them will be drawn from the market. So a very unique step one question could be a person having a history of Prince Medals and China. I think the new name is Viren Tanjina, the coxone inhibitors will almost certainly be contraindicated in that population. Okay, so now we've talked about the coxine inhibitors. Let's go to the ADP receptor blockers.

Okay, remember the ADP receptor is also known as the P2 Y2 receptor, right? So drugs in this class include drugs like clopidogram, it's an irreversible P2 Y2 of blocker, and then there are other drugs that have exotic sounding names like Prasogrel and Ticlopidine and Ticagreler. Those drugs for the most part reversible, right? So the reversible inhibitors of the P2 Y2 receptor. Okay, Ticlopidine, I'll say the big thing you want to know with this drug is it increases a person's risk of TTP thrombotic thrombocytopenic apiopera. Okay, so that's what I'm going to say about the ADP receptor blockers. So let's jump onto the phosphodistory in inhibitors. Okay, in this case I'm going to spend more time with the PD3 inhibitors, right? So the drugs that fall on the other category are drugs like Cylostrozole and Diperidomol. Okay, so these drugs inhibit phosphodistory and by inhibiting PD3 you decrease the breakdown of cyclic AMP. So your cyclic AMP levels actually go up. Okay, and if your cyclic AMP levels go up that hamper's pliclet activation. Okay, now let me just quickly take a quick sidebar and discuss a construct relating to cyclic AMP. Okay, high levels of cyclic AMP causes smooth muscle relaxation. Okay, because remember that elevated levels of cyclic AMP ultimately help you activate myocene inhibits myocene lichen kinase and lead to an adactivation of myocene lichen phosphatines. Okay, so you have smooth muscle relaxation, you get viso-dilation, right?

Because remember that smooth muscle lines the walls of most of our blood vessels. Okay, but cyclic AMP does something totally different in cardiac muscle. In cardiac muscle cyclic AMP actually causes increased contractility. Okay, in a little podcast I'll probably talk about the phospholumban mechanism in cardiac muscle, but that cardiac muscle with high levels of cyclic AMP you get contraction, smooth muscle with high levels of cyclic AMP you get smooth muscle relaxation. Okay, so if we know that high cyclic AMP causes viso-dilation because it causes smooth muscle relaxation you will potentially imagine that you could use a drug like diperedomo. It's a PD3 inhibitor you can use that in cardiac stress tests. Those tests take advantage of the coronary steel principle. I will discuss that coronary steel principle in a later podcast. Seeloster-zol you can actually use it in peripheral arterial disease, okay? So basically by giving that viso-dilator you can open up the blood vessels that feed the lower extremities, okay? So you can relieve that pain, right? In fact it's the only drug that has been shown to improve walking distance in patients that have peripheral arterial disease. Although on your exam if you get a classic description of a person that has PD so, personally in the 60s and the ankle-brechial index is like super low and they ask what's the next best step in management after you've done the ankle-brechial index.

The next thing you want to do is to recommend the walking exercise program, okay? That is the first line treatment for peripheral arterial disease, not seeloster-zol, okay? Not seeloster-zol. So that's all we're going to say about the phosphodistory three inhibitors. The next ones we'll talk about are the GP2 B3 blockers, okay? So these drugs, they block the GP2 B3 receptor. So phybrinogin will have no ability to interact with GP2 B3 A. When you have that you can basically see by-by to quickly aggregation, okay? So the drugs that fall on that is category are drugs like ap 6cimab. There's another drug that starts with an its called epiphybotide and then there is one other drug that's known as tyrophybeth, okay? Again you want to be able to make a parallel between taking these drugs and ITP, right? ITP is basically like a pathologic replication of the pharmacology of these drugs, because remember in ITP you make autoantibodies against GP2 B3 A. And classicly on exams, ITP is tested in the context of systemic lupus erythemathosus, okay? So SLE, okay? So now we've dealt with the drugs that affect primary hemostasis. Let's talk about the drugs that affect secondary hemostasis, okay? Secondary hemostasis. And before we can do that, unfortunately we have to discuss the coagulation cascade, okay? So the coagulation cascade is basically the thing that helps us go from a temporary pleatlet block to a more permanent pleatlet block, okay?

Because if you think about it, I sort of think of it this way. If a person has, if something really bad happens like a natural disaster, right? The first thing you go for is like a quick temporizing measure, right? And then after you seek those temporizing measures, when things sort of stabilize a little bit, you then go for more permanent solutions to whatever problems have been created by the natural disaster. That's the same thing that happens when you get a wound, like some kind of bleed. The first thing that happens is you get viso-construction of the vessels that are filling that side of bleeding, right? Because if you constrict those vessels, you bleed less, right? And that's actually mediated by endothelian. You'll see endothelian make a big comeback when we have the pulmonary pharmacology podcast. But after that, you then have primary hemostasis where you make the temporary pleatlet block, which we've talked about. And then the long term measure is secondary hemostasis, where you basically convert fibroinogen, which is factor 1 to fibroin, which is factor 1 A, which forms a most stable fibroin mesh, okay? So let's discuss the coagulation cascade. They're basically two offshoots of the coagulation cascade. There's the longer one, which is the intrinsic cascade, which we classically follow with the PTT. And then there's the shorter one, which is the extrinsic cascade, which we classically follow with the PTT or INR, okay?

So the intrinsic cascade basically starts with factor 12. Okay? So factor 12 is converted to 12 A. And then factor 12 A converts 11 to 11 A. And then 11 A converts factor 9 to 9 A. And then factor 9 A helps us convert factor 10 to 10 A. But in the process of making that 10 to 10 A conversion, factor 9 A actually uses factor 8 A, as a cofactor. Okay? Factor 8 A is an example of what I will describe later as an accelerating factor, okay? And then when we make factor 10 A, factor 10 A basically helps us convert factor 22 A. But again, in converting factor 22 A, factor 10 A actually uses factor 5 A as a cofactor, okay? So factor 5 A is again something we'll describe as an accelerating factor. Basically accelerating factors are things that help us as cofactors in cleavage reactions of the co-arbolation cascade, right? So factors 8 A and 5 A very high yield accelerating factors. So now we've made factor 2 A. Now factor 2 A can help us create factor 1 to 1 A. Remember factor 1 is Fibrinojane. Factor 1 A is Fibrinojane, okay? Fibrinojane is the more active form of Fibrinojane. Now, one of the job of factor 2, in fact, we say that factor 2 A helps us go from factor 1 to 1 A. Another thing that's done by factor 2 A is to help us convert factors 8 to 8 A and factors 5 to 5 A, okay? That's another job description of factor 2. Another job description for factor 2 A, right?

Which is also known as thrombin, is that it pairs up with a body known as thrombomodulin and that complex to get a help source convert protein C to active a-thed protein C, okay? Remember, a tip-thed protein C is that protein that joins up with its body, protein S, to inhibit factors 8 and 5, okay? To inhibit factors 8 and 5. Very high yield to know that for your step one example. Okay, so that's it for the intrinsic cascade. So let's go ahead and discuss the extrinsic cascade, okay? The extrinsic cascade, again, like I said, we follow that with a PT and INR, okay? And basically, the way the extrinsic cascade works is that your tissue factor, tissue factor is also known as factor 3, that's like mega-loyial for your exam. But basically, tissue factor helps us convert factor 7 to 7 A, okay? And then factor 7 A helps us create factors 10 to 10 A and then 10 A continues the cascade, we already described, okay? And some quick pathology integration here. I remember if you have a deficiency in factor 8, okay? That's hemophilia A, okay? I remember hemophilia A sounds like 8, okay? And basically, remember your PT will be increased, by your PT and your bleeding time will be totally normal. Because remember, factor 8 is a part of the intrinsic cascade, okay? So factor 8 deficiency is known as hemophilia A, is also known as chryspous disease, okay? And remember, it's an excellent, recessive disease, so you should not shopping girls on your exam, if you shop only in boys.

Now, if you have a deficiency of factor 9, right? That's hemophilia B, right? So the pneumonia you learn while you're studying for step 1 is that B sounds like B9, remember the word like B9, like, I mean B9, okay? So hemophilia B, factor 9 deficiency. And again, because factor 9 is a constituent of your intrinsic coagulation cascade, your PT will be increased, but your PT will be normal, and your bleeding time will be normal as well, okay? And again, factor 9 deficiency, hemophilia B is excellent recessive, so you should only shop in boys on your test. Now, if you have a deficiency of factor 11, that is what is known as hemophilia C, okay? And basically, this one does not have excellent recessive inheritance. It has only a rosomal recessive inheritance. So if you get a question on step 1, about a person that has like bleeding into joints or bleeding into soft tissues and they tell you that the PT is elevated, when you see the disorder in a girl, you should have a very good reason for not picking hemophilia C as the underlying pathology, okay? And contrast these hemophilias with vomulibrands disease, right? In vomulibrands disease, you have a deficiency of vomulibrand factor. We say that vomulibrand factor helps us in the adhesion step of primary hemostasis, but it also helps to protect factor 80 serves as a protecting group for factor 8. So basically, in the presence of vomulibrands factor, we actually have an increased half-life of factor 8 in the Sarah.

So if you have VWD, which is a VWF deficiency, your bleeding time will be increased because your platelet is not functioning well. Your platelet count will be normal because remember VWD is a quantitative platelet disorder. It is not a quantitative platelet disorder. And the PT will be increased because you have a decreased half-life of factor 8 in the Sarah, but your PT will be totally normal. And as an aside, remember that your Ristocetine co-factor assay will be abnormal, just like we had in Bernatelier disease, because these are problems with VW Ds, a problem with platelet adhesion in primary hemostasis. And remember that vomulibrands disease is autosomodominant in heritins, and you actually treat that with desmopressin. I remember desmopressin is an ADHD channel log. It increases the release of vomulibrand factor from our wibopaladi buddies in endothelial cells. And just you may be like, why does this make any sense? So think about it. If you vomulibrand factor helps you form clots, and that if you form a clot, you stop bleeding. If you stop bleeding, your blood volume is maintained. So it should sort of make sense that ADH, which has maintenance of blood volume as one of its primary jobs. It should make sense that one of the things it does is to increase the release of something that helps you form clots so you bleed less and maintain blood volume.

And you can actually use a desmopressin in addition to treating vomulibrands disease, you could use it to treat hemophilia A, because again, if you give desmopressin, you increase the release of vomulibrand factor, whatever little factor A to have fluid in the serum, you can increase the half life if you have more vomulibrand factor around. You can also use desmopressin, especially the intranasal form, to treat central diabetes in sepidus. So that's where you basically have failure of the supraoptic nucleus in the hypothalamus, so you're not making it each. So you waste a lot of urine. So hopefully you remember that in the diabetes in sepidus, you have a high serimosmolality and a low urine osmolality because you're not retaining fluid in the urine at the level of the collecting doctor principal cells. Now we've talked about the coagulation cascade. Now let's talk about the anti-coagulants. So basically, drugs that affect secondary hemostasis. So the first drug we're going to talk about is heprin. An ocsaprin is a classic heprin example. Basically, the way these drugs work is that they activate antithrombin 3. And antithrombin 3's job is to inhibit factors 10 and 2. So by inhibiting factors 10 and 2, you do not form clots. So you monitor heprin with a PTT, although here's one thing. Here's one thing your friends at the NBME will love to do to your own exams. Okay? Yes, we monitor heprin with a PTT, but when you're taking heprin, your PTT and your PTT will both be elevated.

Okay? We use PTT to monitor heprin, but remember heprin, we said it activated antithrombin 3 to inhibit factor 10, which granted is a part of the, is actually a part of the common final pathway of the coagulation cascade and factor 2, which is also part of the common final pathway. Okay? So your PTT and your PTT will be elevated when you take heprin. Okay? So if they give you these arrow questions, your PTT should both go up on heprin, not just your PTT. Okay, very high out to know that. And heprin is pretty safe in pregnancy because it's heavily protein bound. So if it's heavily protein bound, it has a very tough time crossing the placenta. Okay? Now, some more higher things would happen, right? So HIT, heprin induced thrombocytopenia. So the classic we present on exams is a person recently got surgery, they got heprin, and then five days later, boom, the plltl account has dropped by 50% or more. If you see that, think about it. Okay? And if this is a first time occurrence, it takes a few days for your plltl account to go down that much. But if you get another heprin product in the future, and you've previously had HIT, you can actually have early onset HIT, where like the problem shop within like a day. Okay? So keep that in mind, that can be a very nice way for them to integrate immunology with heprin. Okay? So what's the pathophysiology of HIT? Basically, the thing that happens is a plltl, let's have a receptor called a plltl factor 4.

Heprin can bind to this plltl factor 4. And that complex of heprin with plltl factor 4 can do two things. Okay? The first thing he can do is he can activate plltl, so again, by activating plltl, you can increase the presence risk of thrombosis. So HIT is actually a hyper-quagulable disorder. The second thing that's done by this heprin plltl factor 4 complex is that your body can actually form autoantibodies against this complex, like IgG. Okay? Remember that IgG has a constant region and that constant region can be bound by an FC gamma receptor that you can find on the surface of macrophages, for example, in the split. Okay? So basically, the thing that happens is macrophages, they use the FC gamma receptor. I believe that receptor is CD56, but I'm not 100 percent. It's either CD6 or CD56, but if I had to guess, I'll see CD56. I'm not really sure to be honest. So, the FC gamma, so let's scratch that then. Let's just say FC gamma receptor binds. I'll try to find out and let you guys know in the next podcast. But basically FC gamma receptor binds the constant region of IgG that's already bound to the complex of heprin and platelet factor 4. And basically, your phagocyte toaster platelet, and that's the mechanism behind the thrombocytopenia that you get in heprin induced thrombocytopenia. Okay? And remember that this is basically a kind of type 2 hypersensitivity reaction, because you're forming autoantibodies against your own cells. Okay? Platelets in this case. Okay?

Now, on your exam, you'll usually ask for the next best step in management in a person that has HIT. The first thing you want to do is to obviously stop the heprin. Okay? But do not give them any other heprin product in the future. Classic exam answers to offer like, oh, offer a low molecular with heprin. Yes, the risk of HIT is low with low molecular with heprin, but it's not zero. Okay? So, giving low molecular with heprin is never the right answer as a treatment for HIT. The treatment for HIT, classicly on exams, the more common answer choice, is to give a factor 2 inhibitor. Okay? Those are called direct thrombin inhibitors. So, drugs like leperidine, bivaliridine, dabygatron, and agatrobat. Okay? I repeat those again. Leperidine, bivaliridine, dabygatron, agatrobat. Okay? They have factor 2 inhibitors. Alternatively, you can give factor 10 inhibitors. Right? So, you can give drugs like a pixaban and riveroxaba. Remember, those drugs have XA in the name. So, that helps you remember that they are factor 10 A inhibitors. Okay? Now, one quick thing I'll just go ahead and say is these factor, these are factor 2, factor 10 inhibitors. Classically, the teaching was that, hmm, none of these drugs are reversible. You cannot reverse any of the adelitrious effects, like let's see a person starts bleeding on agatrobat. Oh, there's nothing you can do. It so happens that dabygatron, right? dabygatron is actually now reversible.

If you've ever worked in a hospital, dabygatron is known as predaxa. There is now a monoclonal antibody against predaxa. It's called Praxbind. That's the trade name. But the actual drug name is it's a monoclonal antibody. It's known as a dyrosisumap. That is certainly something you want to know for your exam. Pretty certain. I've seen that in the 2018 version of first aid for the USMLE step one. So, just don't forget that. Okay? So, dabygatron is now in factor reversible with a drug known as a dyrosisumap. So, that's it for head. Okay? And the last thing I'll say about heparin. Before we jump to low molecular with heparin, is that if a person is bleeding from heparin, they have like heparin toxicity. You go ahead and give them predominant sulfate. Okay? Predominant sulfate is a positively charged molecule. It binds up negatively charged a heparin. Okay? And heparin, you can actually use this to treat antifusible lipid and tibody syndrome. Okay? Because that's a problem that classically shows up in pregnant women. A pregnant woman should not be put on warframe. Okay? So, you give something that's if in pregnancy, like heparin, they classically give it in the belly. Okay? So, low molecular with heparin, I'm not going to see much else here. Basically, it activates antithromine 3, just like regular unfractionated heparin. But it activates antithromine 3 primarily to inhibit factor 10. Okay?

And instead of using the PTT to monitor low molecular with heparin, you can actually do a factor 10 activity. Okay? That's how you monitor low molecular with heparin. Okay? And just that aside with antithromine 3, remember that antithromine 3 is one of the proteins that you lose in the urine in a ferric syndrome. Okay? That's why a ferric syndrome is a pro-thrombotic state. Okay? So, one classic thrombotic effect that they could test on exams relating to the nephrodix syndrome, like membranocnephropathy, for example, is if they describe a person that has membranocnephropathy or any other kind of nephrodix syndrome and then they present with flank pain, sodium onset flank pain, you really want to think about renoving thrombosis with that. Again, the thought is by losing antithromine 3 in the serum, you have less inhibition of factor 10 and 2, so you form more clots. Okay? And while we're on the subject of thrombosis, another aside, I guess, a sidebar is that you should also associate splining vein thrombosis with as a complication of pancreatitis. Okay? It's just one of those things you want to file away in your mind. And then another kind of thrombosis, you can also file away in your mind while we're on this subject is hepatic vein thrombosis, right? That's borkiaris syndrome. Classically on exams, they test that in the context of people that have like polycythemia vera. Remember the association of that with a jaqutry mutation?

It's also common in people that take, I mean, it's like super, but it's pretty common on exams. You should also remember the association of people that are taking like OC Ps. Okay? OC Ps, especially present that takes OC Ps and is a smoker. Think about if they present with like right upper quadrant pain, sodium onset and we have like like, like, ascites and all that stuff from poor hypertension. Think about borkiaris syndrome. Okay? Borkiaris syndrome. That's thrombosis of the hepatic vein. Okay? Very high. You also know those thrombosis syndrome. So now we're done with a heparin. Let's go ahead and talk about a warframe. Okay? So warframe, give you a quick preamble first. Okay? So basically factors 279 and 10 and protein CNS. All these proteins require gamma caboxylation to make the active forms. Okay? So if you want to make activated, factors 279 and 10 and protein CNS, you do need to gamma caboxylate them. Okay? And that gamma caboxylation is done by reduced vitamin K. Vitamin K acts as a co-factor for that gamma caboxylation. Okay? But because it's a reduced reaction, right? As you use reduced vitamin K for the reaction, it's ultimately converted to oxidized vitamin K. So if you want that reaction to go in the future, you want to take that oxidized vitamin K and get it right back to reduced vitamin K. Okay? The enzyme that helps you go from oxidized to reduced vitamin K is an enzyme known as vitamin K epoxide reductase. Okay? Vitamin K epoxide reductase.

So the way warframe works is that it inhibits vitamin K epoxide reductase. If you inhibit vitamin K epoxide reductase, you do not regenerate, reduce vitamin K. So you're basically not regenerating a co-factor for the gamma caboxylation of factors 279 and 10 and protein CNS. That is how warframe exerts its anti-quagulant effect. Okay? So remember, activated protein. So a few more things with that, some other things they can test with warframe is that remember that activated protein C helps you inhibit factors 5 and 8. Okay? And remember I said that to make that activated protein C, you need factor 2 A thrombin, pairing up with a body thrombomodulate. Okay? To convert protein C to activated protein C. Okay? And then activated protein C pairs up with protein S as a co-factor and that helps you inhibit factors 8 and 5, which as we said, you accelerate in factors. Okay? So if you really think back to what I've said earlier, this is sort of like a negative feedback mechanism of factor 2 on the activation of the accelerating factors because remember factor 2 activates factors 8 and 5, what in addition factor 2 activates protein C to help you go back and inhibit factors 8 and 5. Okay? So just some nice time there. So the thing is factors 279 and 10, right? They are pro-quagulants. Okay? They have a long half-life. Contrars that with protein CNS, they are anti-quagulants and they have a short half-life.

So in the first few days after a person gets war-free, the anti-quagulant effect actually goes away first. Okay? So you have a transient pro-quagulant state because again remember the anti-quagulant's protein CNS have a short half-life than the pro-quagulants factors 279 and 10. Okay? So in the first few days while a person is getting war-free, you do need to bridge those people with hepros. Okay? So that you can take care of their transient hyper-quagulant state because factors 279 and 10 have a longer half-life than protein CNS. But if a person, for example, they want to make a question really hard and they say, oh, a person is about to put in war-free and they have a history of HIT. Instead of bridging them with heprin, you can bridge them with a factor two or factor ten directing himeter. Okay? Now one of the derivative concepts with this is what if they give you a question about a person that has a protein C deficiency or protein S deficiency? The thing is if those people already have that deficiency, when they take war-free, it's like that minute anti-quagulant effect you get from protein CNS before the dropout of circulation, it's no longer there. So those people actually have a much higher risk of hyper-quagulability like transient hyper-quagulability side effects with war-free. Okay? Classically, on exams, they test people that have protein CNS deficiency as getting skin necrosis after a recent administration of war-free. Okay? Very high up to know that.

Now, how do you reverse the effects of war-free? Well, if you can wait a couple of days, you can give vitamin K, okay? But if you need very quick reversal, you can actually go ahead and give a fresh-fersun plasma. Okay? You give a fresh-fersun plasma. Okay? Fresh-fersun plasma can help you very quickly. Reverse war-free is a effects because it contains activated forms of the clotting factors that have been clobbered by the administration of war-free. Okay? So that's it with war-free. So Toronto, we'll just talk about a few more drugs real quick. So let's talk about the clot-busters. Your clot-busters include drugs like altiplis, retoplees, and tenecta-plees. Okay? So these drugs are clot-busters. They all have pleas in their name. Although I guess a streptokinase is another one you can think about. So these drugs, they basically aid the conversion of plasma inocene to plasma. And then plasma in goes and cleaves thrombin and fibrin clots. Okay? So when you give these drugs, obviously your PT and PT will go up, right? Because whatever clots your PT and PT going up, why would your PT and PT go up? Actually I think that is, I don't think your PT and PT will go with these drugs. Because they are working after you've formed a clot, not before you form the clot. Yeah. So your PT and PT, I may be wrong on this. So I'll have to look this up. But I would prognostic it. That PT and PT does not go up when a person takes a clot-busting drug.

I would imagine that your PT and PT should be unaffected if I'm just reasoning with peer physiology. So I guess I have two things to discuss at the next podcast. What happens to PT and PT and a person takes a clot-boster and what is the FC gamma receptor for platelets? Oops, not for platelets. For IGG, is it CV16 or CV56? Those are two things I will address at the next podcast or some future podcast. Okay. So those are your clot-busting drugs. Okay? If you want to reverse these drugs, so let's see, you've given a person a clot-boster, they're bleeding everywhere. For example, let's see, they had a PE, give them the clot-boster, they're bleeding like no man's business. The way you can reverse those drugs is to give drugs like aminocaperic acid or try an exameic acid. Okay? You can use those to reverse the clot-busting effects of auto-pleas, retoplesa, tenectoplesa, and streptokinesis. Okay? And actually, and an usual exam question you could get is a person that has like excessive postmenopausal bleeding or very nasty menoraja, you can actually give trinexamic acid to basically prevent the body from breaking down clots so that you can sort of stop the bleeding. So that's an unusual question you could get on your board exams. Also something that may show up on an ube-gung shelf in your third year or in step two or in step three. Who knows? Okay. So another drug I'll talk about is aculesumap. Aculesumap is monoclonal antibody against C5. Okay?

Remember, C5 B through C9 help you from the membrane attack complex that basically blows holes in cells. Okay? So aculesumap, it's a monoclonal against C5. It prevents the membrane attack complex from forming so you do not explode cells. Now, what is aculesumap used for? Aculesumap is actually used to treat PNH, paroxysimon, nocturnal hemoglobinuria, and let's just quickly discuss the pathophysiology of this problem. Okay? In PNH, you basically have a PG-A gene mutation. Okay? PG-A the gene, if you unscribe those letters, PG, at least unscribe a big, big, if you unscribe the letters, you get GPI. Okay? The PG-A gene encodes the protein products which are GPI anchors. Okay? These GPI anchors are basically flagposts for stuff on the surface of your cells. Okay? So some important stuff on the surface of your red cells, for example, are things like CD55, which is known as decay accelerating factor and CD59. Okay? These two things, basically help prevent complement from exploding your red cells. Okay? So if you have a mutation, or I guess a deficiency in these GPI anchors, you don't have CD55 and CD59 on the surface of your red cells. Your red cells will explode. Okay? And you will get an intravascular hemolosis. Right? So hopefully, remember the markers you have within intravascular hemolosis. Right? So you have a decrease in your Haptoglobin. You have an uncondugated hyperbilarubinemia. Okay? So sort of things, I guess, to keep in mind with that. Okay?

So, classicalian exams, this shows up as a young guy that has like a lot of red urine in the morning. And you may be wondering, why is this person forming red urine in the morning? Like, do they not form red urine at other points in the day? They do. They're actually from red urine at other points in the day. But they just form more in the morning because the thing is when you sleep, you're hypowyntile, you're not like sleeping and doing like, it's only if you have like a nightmare or you're doing something that I think you can imagine. I'm not gonna mention it. But basically, if you hypowyntile that you're sleeping, you'll get a respiratory acidosis, your blood pH falls, a reduced blood pH actually activates complement. Okay? So if you activate complement more while you sleep, you have more intravascular hemolosis because you have PNH. So you form more red urine in the morning. Okay? So that's the mechanism behind that. So if a person had sleep apnea, for example, right? They potentially have more intravascular hemolosis in PNH. So I guess another like weird association to keep in mind. So the way you treat PNH is to prevent that membrane attack complex from aggregating a urac cell by forming a monoclonal against C5. Okay? That's how EQLUSU map works. It's an extremely expensive drug. Costs hundreds of thousands of dollars per year. What it basically cares, PNH, it basically makes you live as long as like a normal human being. So it's a blockbuster drug. Okay.

Now just some quick like one word association to round this up. If a person has like anemia of chronic disease or anemia from like kidney failure, you want to go ahead and give those people ipo, right? Occasionally, they call it like erythropoietin or double poietin on exams. Double poietin is an ipo analog. Okay? And please, you know what I'll mention that in a little podcast, let me let that go for now. Another classic example question, a person is getting chemo and you knock down their white cells. The way you can spruce those people's white cell numbers back up, you can give a drug like a philgrass stem. Philgrass stem is a GCSF analog. So granulocyte, colonist, immune leading factor analog. So it spurses up your neutrophil counts. Alternatively, you can give sagramoste. Sagramoste means a GM CSF analog, right? So it's a granulocyte, monocyte, commonly colonist, immune leading factor analog. Okay? That's used more for leukopenia. Okay? Versus philgrass stem that is used more for a neutropenia. Okay? And then if a person has a low-plitlet count, let's say they had like some kind of plastic anemia or whatever, you can give them an interlookin 11 analog because remember IL 11 helps your mega-carrier sites different sheet. So the person has severe thrombocytopenia. You can give an interlookin 11 analog like oprovican. Okay? Oprovican. So I think that's all I'm going to say with him from ecology. I will make another podcast down the line that covers onc from ecology.

But I personally think that if you know everything in this podcast, you know everything you need to know within reason for him from ecology, for your board exams and for the future. So I wish all the best as you study and I'll see you at the next podcast. Have a wonderful day and stay blessed.

Endothelial cell Weibel-Palade bodies and platelet alpha granules.

Von Willebrand Disease (VWD).

COX-1 is constitutively expressed (e.g., GI mucosa), while COX-2 is inducible (e.g., inflammation).

PDE inhibitors (e.g., Cilostazol, Dipyridamole).

It inhibits Vitamin K epoxide reductase, preventing the regeneration of reduced Vitamin K, thereby impairing $\gamma$-carboxylation of Factors II, VII, IX, and X.

Desmopressin (DDAVP).

Factor VII Ia and Factor X Ia.

Activated Partial Thromboplastin Time (aPTT) (Intrinsic pathway defect).

It potentiates Antithrombin III's ability to inhibit Factors Xa and II.

Argatroban or Bivalirudin (or Dabigatran, though the latter is a direct factor II inhibitor).

Antithrombin III (leading to increased clotting risk/thrombosis).

Because low molecular weight heparin is contraindicated, and direct thrombin or Factor Xa inhibitors should be used instead.

Factor VII Ia and Factor X Ia.

Activated Partial Thromboplastin Time (aPTT) (Intrinsic pathway defect).

It potentiates Antithrombin III's ability to inhibit Factors Xa and II.

Argatroban or Bivalirudin (or Dabigatran, though the latter is a direct factor II inhibitor).

Antithrombin III (leading to increased clotting risk/thrombosis).

Because low molecular weight heparin is contraindicated, and direct thrombin or Factor Xa inhibitors should be used instead.