Transcription
It's Medicos is perfection. Alice, once again continuing our discussion on bleeding and coagulation disorders. We have started talking about fibrinolysis in the previous video. We have talked about tissue plasminogen activator. Today, we will talk about the clinical uses of TPA. TPA, which comes from the injured endothelium, not the smooth endothelium, helps converting plasminogen into plasmin. Plasmin will destroy the fibrin clot. With that being said, now let's get started. [Music]
Quick sample of my previous videos on bleeding and coagulation, just to let you know that you are living under a rock. Now subscribe. Hemostasis, or prevention of blood loss, has many steps. We have talked about vasoconstriction, temporary plays plug, coagulation. We're talking about fibrinolysis now. Plasminogen to plasmin, thanks to TPA, which will activate plasminogen to plasmin. Then plasmin will activate TPA, which converts plasminogen to plasmin. Plasmin is acting in its self-interest. Plasminogen to plasmin, thanks to thrombin, TPA, gyro kinase 1, 2, and 11, and collectin. Plasmin now is active, convert fibrinogen degradation products, stabilized fibrin to D-dimer. Cool. Inhibits plasmin: the alpha 2 antiplasmin, alpha 2 macroglobulin, who will inhibit TPA. Plasminogen activator inhibitor 1 and 2. If it weren't for TPA, many minute clots would clog several small vessels all over your body until you die. So here's the whole story: intrinsic or extrinsic pathway activating the prothrombinase complex, activating prothrombin to thrombin, thrombin cleaving fibrinogen to fibrin. Plasminogen is getting incorporated into the fiber and fibers. TPA activates plasminogen to plasmin. TPA comes from the injured endothelium. Plasmin is active, converts fibrin into fibrin degradation products, which are soluble fiber, going into fibrin degradation products, which are soluble, and the fiber, the stabilized fiber into the D-dimer.
If you can't explain it simply, you don't understand it well enough. So let's use the KISS principle: keep it simple, stupid. There are two types of plasminogen activators: tissue type plasminogen activator (TPA) and urokinase type plasminogen activator (UPA). Now we're talking TPA. Get my 50 hematology cases before you die by going to patreon.com/photo/minicoasters. They cover many topics, including bleeding and coagulation disorders. I've talked about this crazy positive feedback loop in the previous video. Just remember, both plasminogen and TPA bind fibrin to form a ternary complex, which means three parts. This will help us manage activation and forming plasmin. Two types of formation activators: TPA and UPA. We have the natural TPA and the recombinant TPA through the recombinant DNA technology. We have streptokinase, which comes from bacteria. Which bacteria? It's called streptokinase. It comes from the streptococci or cox i, or whatever you want to call it. Streptokinase, less effective, why? It's allergic. It can cause transient hypotension, plus other stuff. We're gonna talk about that. We have an extra place, which is an acylated plasminogen streptokinase activator complex, which means we got a streptokinase and we got a plasminogen activator and halfs like an acyl group and form a complex. So it's basically a modified streptokinase. Alteplase, or it applies to negative place. This most hapless, all these are recombinant TPAs.
Clinical use of TPA: they're called clot-slicing drugs, or clot busters, or thrombolytics, or fibrinolytics. Uses: MI, stroke, specially ischemic. Never use TPA in hemorrhagic strokes, only in ischemic strokes. How do I tell the difference between an ischemic and hemorrhagic stroke? CT scan of the head without contrast. Clinical uses of TPA: we call this clot lysing, clot busters, thrombolytic, fibrinolytic therapy. It's called clot buster, not to be confused with blockbuster. Coronary artery occlusion, big time, acute myocardial infarction. The earlier the better, within 4 hours. Don't wait, it's urgent. Time is money, as Benjamin Franklin said. Ischemic stroke: thrombotic or embolic, those are ischemic strokes. Never use TPA in hemorrhagic strokes. Pulmonary embolism: accelerate the emboli resolution, again within the first 24 hours, the earlier the better. You are in the hour number 23. Don't say, oh, we have another hour, we can drink tea. Shut up. The earlier the better. To wait 24 hours like three hours, two hours, the earlier the better.
Catheter-directed chemical thrombolysis into the clot. The chemical here being TPA. We have a vessel here, let's say this is an artery, and it has a clot. We will introduce a catheter into the clot. This catheter contains a chemical. This chemical is called, hello, TPA. This TPA is a fibrinolytic drug. It will lysis the fibrin. Makes perfect sense. Again, the earlier the better. Can be used in low output cardiac failure, cardiogenic shock due to blocked coronary artery. Yes, when and when the artery is occluded, poke it with the catheter, man, and cover the catheter with TPA. This is the complete crime. We call the stuff intravascular thrombolysis. Next: thrombolytic for PNH patient, paroxysmal nocturnal hemoglobinuria. We've talked about in a great, one of my most like famous and significant videos of all time. Why? Because PNH patients are more prone to clots, so they are prone to clots. Use a thrombolytic therapy. Strokes. Let's talk about strokes. Stroke is divided into ischemic stroke, hemorrhagic stroke. Ischemic due to occlusion of an artery going to your brain. Hello, hemorrhagic is bleeding into your brain. So here's the artery occluded, and here's the artery bleeding. It bursts, it is bleeding all over the place. How to differentiate between the two? Head CT scan without contrast. Very, very important. Because if you assume that the patient has ischemic stroke and you gave the patient TPA, turns out it's a hemorrhagic stroke and you gave the patient TPA, the patient is gonna bleed into the brain. Hello, stupid, wake up. Order a head CT scan without contrast. Ischemic stroke due to occlusion is divided into focal and global. Focal means like a certain location, and global many places. Toyota, let's go places. The focal is divided into TIA and ischemic stroke. The ischemic stroke can be thrombotic, embolic, and lacunar. We'll talk about strokes in greater detail when we talk about neurology in the near future.
The most common use of TPA is ischemic stroke. First, don't forget to order a non-contrast CT scan of the head to rule out hemorrhagic stroke because TPA is contraindicated in hemorrhagic strokes. Used to be an idiot. How should we give TPA? You have two options: locally or systemically. Locally means in a catheter. Remember the artery, the artery had a clot. We introduced a catheter covered by a chemical. The chemical is TPA. We call this catheter-directed chemical thrombolysis into the clot, or systemically by intravenous injection. It's a very expensive injection because it saves lives, man. When it saves lives, it will have a higher demand. When you have a higher demand, what will happen to the price? It will go up. This is called economics 101, the study of scarce resources which have alternative uses. Everything in your body is on a balance. If you have too little TPA, you will clot because TPA is fibrinolytic. If you don't have TPA, don't have fibrinolysis, fibrin will grow and grow and grow. You will have lots of clotting. This is called hypofibrinolysis. Too much TPA, on the other hand, you have hyperfibrinolysis. You have fibrinolysis, utilize the fibrinolysis, but fibrinolysis to fibrin, and then you bleed. We call this systemic lytic state. Also, if you have lots of TPA, TPA will increase vessel permeability.
This is the most important slide in this lecture. Pay attention. Leave the phone and pay attention. To types of plasminogen: we have plasminogen which is incorporated into the fibrin, also known as the plasminogen that's bound to the fibrin, or fibrin-bound plasminogen, and we have the circulating plasminogen that's just floating around freely. This one is activated. We'll have fibrinolysis that's localized in one location and one location only. If this circulating plasminogen is activated, we'll have a systemic lytic. We will have plasmin floating around destroying clots all over your body, even the useful minute clots due to trauma. This will lead to systemic lytic state, degradation of fibrinogen and fibrin everywhere, increasing your risk of bleeding. So localized fibrinolysis is good. Systemic lytic state is horrible. Therefore, TPA drugs are divided into two classes: fibrin-specific plasminogen activators and non-specific or non-fibrin-specific plasminogen activators. These drugs only are going to activate the plasminogen that's incorporated into the fibrin; in other words, only the localized plasminogen. These drugs will work or will activate the plasminogen that's circulating in the plasma, every single plasminogen. Which class of drug has less side effects? Answer: these ones. Why? Because they only work local, which is what we like, because localized fibrinolysis is good, but systemic fibrinolysis is evil. Which class do you think will be more expensive? Answer: the fibrin-specific. Why? Because there is a lower risk of bleeding via the systemic lytic state. Now you know how to refute the argument of the buffoon who says those big pharmaceutical corporations just keep increasing their prices to whatever the traffic will bear. No, sir. If you have two brain cells that fire, you would realize that if one class is more expensive for no reason, then all the hospitals will use the cheaper class and drive all of these greedy bastards out of business. Think, people, think. That's why you need to calm down and study economics, the study of scarce resources which have alternative uses. Streptokinase was a fibrin-specific or non-fibrin-specific? Non-fibrin-specific. So it's relatively less expensive than the fibrin-specific, and it will have side effects. Let's see: first of all, allergic reaction, 5% of the patients just like right out of the door, and transient hypotension. We'll discuss this later. It's not an enzyme, therefore it can't directly activate plasminogen to plasmin. Just because you have an -ase doesn't mean you're an enzyme. Pain. Sometimes biochemistry professors like, give me an example of something that ends in an -ase and is not an enzyme. Give them streptokinase and shut them up instead. It forms a complex with plasminogen, leading to a conformational change to the plasminogen. This will lead to exposure of the active site of plasminogen. Now TPA or streptokinase going to work on it, activating it into plasmin, and boom, we have the great plasmin. This complex is fibrin non-specific. Translation: they will activate plasminogen that's incorporated, which is localized, and the circulating plasminogen, which is all over the place. This is good. This will lead to systemic lytic state, increase the risk of bleeding. When you take streptokinase, patients may develop antibodies against streptokinase. They need to decrease effectiveness of the drug. Patients with prior streptococcal infection, because remember I've told you that streptokinase comes from this streptococci, may develop antibodies against streptokinase. No kidding. We need to decrease effectiveness. In short, streptokinase is not that good. It's not that cracked up to be. Now you know why there are other classes of drugs that are more expensive. Now we understand why the use of streptokinase is limited or non-existent in the United States. It's not a conspiracy theory, it's science. The more expensive class of medications are fibrin-specific plasminogen activators, so less risk of bleeding, less risk of allergic reaction.
Contraindications of TPA: when not to give TPA. We have absolute contraindications and relative contraindications, which are more important, of course. The absolute: previous hemorrhagic stroke at any time in your life. I had a hemorrhagic stroke 20 years ago. I will never give you TPA, but very like it was like ancient history. I don't care if you have it before. It's an absolute contraindication. I don't want you to bleed into your brain, man. I care about you. Other cerebrovascular events in the last year, including the ischemic stroke. So if you have ischemic stroke during the last year, I will never give you TPA. However, if you had an ischemic stroke 57 years ago, I still can give you TPA. Active internal bleeding. If you are bleeding right now, don't give TPA. Intracranial neoplasm. Of course, if there is a neoplasm, your brain is under pressure, increased intracranial pressure. Don't give anything that will lead to bleeding because this brain is eager to bleed when it has a neoplasm. Suspected aortic dissection. Because when there is an aorta here and here is a dissection, we need the blood to clot. Okay, actually, blood clot in case of aortic dissection is a great thing. It's a good thing. If you add something that's fibrinolytic, okay, welcome to that dissection. Relative contraindication: persistent hypertension, which is very high, 180 over 100 millimeters of mercury. Current anticoagulant use with a high INR, higher than 2 to 3. Remote non-hemorrhagic CVA, cerebral vascular accident. We're talking about ischemic strokes here. If it's remote, if it's like 20 years ago, 10 years ago, five years ago, you can give TPA, no problem. Recent major surgical procedures. I had an open heart surgery three days ago. Stay away from TPA. Major trauma, two to four weeks. I had a car accident like two weeks ago. Stay away from TPA. Previous streptokinase exposure. Okay, because again, allergy, or you can have hemorrhage. Active peptic ulcer or, by the way, so it's we have many reasons. Could be allergy, we're trying to prevent allergy, could be try to prevent the antibodies that we have against the streptokinase, and also decrease the risk of bleeding. Active peptic ulcer and pregnancy. Those are relative contraindications. Okay.
Some quick notes: do not give ACS patients, acute coronary syndrome patients, with TPA with no ST elevation. Translation: let's say you have a patient with acute coronary syndrome, the ST is not elevated, don't give TPA. It's less efficient. Percutaneous coronary interventions are superior to fibrinolytic therapy. So yeah, if you have two options, you have the percutaneous coronary intervention. If you want to poke the coronary artery, the clot in the coronary artery with a catheter, this is your first option. The second option is to give TPA in a patient with a coronary artery disease or an acute myocardial infarction. Which one is better? Poke it, baby, poke it. That's it for today. Thank you so much for watching. Please subscribe and hit the bell for me. On Facebook and Instagram, I am posting lots of cases on Facebook. You can get all of my notes and all of my cases, like I have 50 hematology cases, by going to patreon.com/scishow. That's perfect nails where medicine makes perfect sense.