Transcription
Hey guys, it's Medicos. Is perfection animals? One more time, we have started talking about fibrinolysis in our series about bleeding and coagulation. We talked about fibrinolysis and plasminogen and plasmin, but today let's talk about the real hero: the tissue plasminogen activator, or TPA. The one that converts plasminogen to plasmin. Then plasmin will break the fibrin clot, and everything will return back to normal, hopefully.
With that being said, now let's get started. But before we get started, where do you think the TPA comes from? From the endothelium, right? Do you mean the healthy, smooth endothelium? Wrong. From the injured, traumatized endothelium. Life is rough, man. [Music]
So here's just a sample of my previous videos on bleeding and coagulation. That's why you need to subscribe and save this playlist: Hemostasis as the stoppage of blood loss, or prevention of blood loss. It has many steps: vasoconstriction, temporary platelet plug or primary hemostasis, coagulation or the thrombus—the secondary hemostasis—then fibrinolysis, or as Merriam-Webster says, fibrinolysis. Then regeneration and repair. We have talked about vasoconstriction, temporal plug, and coagulation before, and we are now talking about fibrinolysis. Fibrinolysis. Fibrin is the protein which is made of fibers. Lysis is to break down, AKA to beat the crap out of the clot, man. Forgive my language. Life is rough.
What's the goal of fibrinolysis? What's the *why*? Because Friedrich Nietzsche said, "He who has a why to live can bear almost any how," and Medicos says, "He who has a why to fibrinolysis can bear almost any mechanism." Fibrinolysis—the *why*. Why do you do that? Because if you leave the clot alone, it will grow and grow and grow and press on the structure, occlude vessels, and tell you to die. Too much of anything is problematic, so you better break this clot down after it has done its job and drawn its course. Fibrinolysis has two types: primary and secondary. Primaries physiology, which we are talking about right now. We're going to talk about diseases; this is secondary fibrinolysis. So primary fibrinolysis. Now we know the *why*, let's discuss the *how*. Which enzyme breaks down the clot? The greatest of all time: plasmin. Then what? Then the clot is broken down into degradation products, which are soluble fragments, cleared by your sewage system—liver and kidney. Where does plasmin come from? From plasminogen. Plasminogen will give us plasmin. And we need a protease, why? Because these guys are proteins. Protease: an enzyme that digests protein. How does this protease digest plasminogen into plasmin? By cleaving the arginine-valine bond. If you want to be super sophisticated, memorize this crap. What protease are you talking about? I'm talking about the great tissue plasminogen activator. So we activated plasminogen to plasmin thanks to TPA. Now what? What will plasmin do? A lot. Digest fibrin into fibrin degradation products. They disappear. Energy into fibrin degradation products. All digest 5 & 8 & 2 & 12. 5 & 8, 2, and 12. If you undescribed plasmin, just one word: hypocoagulability. If you leave this crazy plasmin free all the time, it will degrade every single blood clot in your body. You will never form a useful clot, even when you injure yourself, which will lead to bleeding until you die. That's why we need checks and balances. Put this crazy act of plasmin in a precursor, inactive form called plasminogen. And then we need an enzyme to convert those measures into plasmin. We can regulate this step because this is the most important step. This takes a few days, and that's good. Why? Because we need time for this fibrin to grow, form a nice cloth, stop the bleeding. And once you stop the bleeding, let's break this clot down and regenerate the tissue to maintain or to restore the blood flow and back to normal.
Plasminogen, also known as profibrinolysin, which means that the plasmin is called fibrin lysin. Let's talk about plasminogen. Plasminogen: is it active? Yes, it's active. Therefore, it's a protein; therefore, it's made in the liver. It's a zymogen, which means it's a proenzyme; the enzyme here being the plasmin. Then what? Plasminogen floats in the plasma, then gets incorporated into the blood clot, into the fibrin during the fibrin formation. That's why I call it plasminogen ink. Now this plasminogen, which is incorporated in the fibrin, is activated by TPA, which comes from now the smooth endothelium, the injured, traumatized endothelium, which takes days. Then plasmin, here the crazy active guy, degrading fibrin into fibrin degradation products, degrading fibrinogen into fibrin degradation products, degrading the stabilized fibrin into the D-dimer after the clot is formed. Plasminogen, which was incorporated into the clot, is converted into plasmin that turns around and aids the clot. As William Shakespeare said, "Et tu, Brute?" when he killed Julius Caesar. If it weren't for TPA, many minute clots would clog several small vessels until he died. I mean several, like millions of clots. Even though the endothelium is traumatized, it can produce the glorious TPA to save our lives. Thank you, endothelium.
Great news, guys. I have 50 hematology cases on my Patreon page. Please go to patreon.com/scishowinkosis and get all of these cases. Some of them are really difficult. They cover bleeding and coagulation disorders. By the way, plasminogen to plasmin thanks to TPA or urokinase. Plasmin will turn around and activate the TPA urokinase, which will convert plasminogen to plasmin, which will activate TPA, which will like to propose an into plasmin, acting in its self-interest. Plasminogen to plasmin thanks to thrombin, TPA, urokinase, factors 11, 12, and collegen in the free plasma here will convert fibrinogen to fibrin, fibrin into fibrin degradation products, fibrinogen into fibrin degradation products, stabilized fibrin into the D-dimer. Who will inhibit this crazy guy? Alpha-2 antiplasmin, alpha-2 macroglobulin, any free plasmin. And please remember: free, not incorporated, free plasmin will bind the alpha-2 antiplasmin. When it binds the alpha-2 antiplasmin, they destroy the plasmin. Here is the full story. Have the intrinsic and the extrinsic coagulation pathways activating the prothrombinase complex, which will activate prothrombin into thrombin, and thrombin into fibrin. Fibrin is being stabilized by factor 13 into the active, stabilized fibrin thanks to cross-linking. Now that's secondary hemostasis. Let's go to fibrinolysis. We have the plasminogen gets incorporated while we are forming the freakin' clot. It's incorporated within the fibrin fibers. Then the TPA comes from the injured endothelium, or the urokinase which comes from the liver. Okay. I think into plasmin. Plasmin will convert fibrin into the degradation products and fibrinogen into fibrin degradation products and the stabilized fibrin into D-dimers. Also, all digest factors 5 & 8, 2, and 12. Both plasminogen and TPA bind to fibrin, which I called they get incorporated into fibrin, forming a ternary complex. This will help plasminogen activation into plasmin. Please don't forget this ternary complex. And by the way, ternary means 3. Albert Einstein said, "If you can't explain it simply, you don't understand it well enough." So let's explain simply. There are two types of plasminogen activators: we have the tissue type plasminogen activator, or TPA, which is the topic of today's video, and the urokinase type plasminogen activator, or the UPA, which was first discovered in human urine. Yikes.
For the last time, TPA activates plasminogen to plasmin. Where was the plasminogen? It was incorporated into the fibrin fibers together with the TPA and the fibrin. We have three structures: plasminogen, TPA, and fibrin. They will combine together, forming the ternary complex, will activate plasminogen to plasmin, and will degrade the fibrin into fibrin degradation products, the fibrinogen into fibrin degradation products, the stabilized fibrin into the dimer. If you knock out TPA and urokinase genes from the mice or rat—let's knock the TPA out—now plasmin is not gonna get activated, the clot is never will never get destroyed. This will lead to spontaneous deposition of extensive fibrin meshwork. No wonder, because nobody is destroying this fibrin. The positive feedback loop: as plasmin degrades the fibrin, so here's plasminogen to plasmin, plasmin degrades the fibrin, the C-terminus on the fibrin gets exposed. This C-terminus contains lysine residue that binds plasminogen and TPA, converted into plasmin. The grace fibrin, the lysine residue is exposed. TPA, plasmin, degraded fibrin, more fibrinogen, it's more fibrinolysis, more fibrinolysis. There are two types: plasminogen activators—TPA and UPA. Also, we have recombinant TPA, which is made through their recombinant DNA technology, and we have the streptokinase, which comes from bacteria. TPA drugs. Drugs that contain TPA, streptokinase, which comes from bacteria, it's less effective, usually used outside of the United States. So some nuts will say, because of the big corporations, the big pharmaceutical corporations are keeping them out so that they can sell us more expensive drugs. Shut up. In the next video, I'll tell you why this person is an idiot. Alteplase, reteplase, tenecteplase—those are the recombinant tissue plasminogen activators. Clinical uses of TPA will be discussed in detail in the next video, but for now, remember they are clot-lacing drugs. The layman will call it open-heart surgery; the sophisticated will call it coronary artery bypass graft. This will increase TPA level in your plasma for some reason, which will convert plasminogen to plasmin, more fibrinolysis will end and bleeding. In the next video, we'll talk about clinical uses of TPA, but for now, let me leave you with a question: What's the antidote for TPA? Let's say that you're a crazy doctor, you gave too much TPA to the patient, and now the patient is bleeding. How would you reverse that? What's the antidote? This is the first question. Second question: What are the contraindications of TPA use? Please subscribe and hit the bell to get notifications, because subscriptions don't mean anything anymore. Follow me on Facebook and Instagram. Get all of my notes and my cases in my private Dropbox links when you go to patreon.com/scishow. Thank you so much for watching. This is Mythical Sister Fiction. A loss for medicine makes perfect sense until next time. Be safe, stay happy, and study hard.