Transcription
It's a good day, and this is your favorite medical channel, Medicos is Perfection. Alice, continuing our discussion on bleeding and coagulation disorders. We have started talking about fibrinolysis before today; we'll talk about plasminogen activator inhibitor, or PAI. We have PAI-1, which comes from the endothelium and adipose tissue, as well as PAI-2, which comes from the placenta. With that being said, now let's get started. [Music]
As you know, hemostasis is the process of prevention of blood loss, or stopping the bleeding, and consists of main steps: vasoconstriction, temporarily; blood coagulation; and fibrinolysis. We are here: plasminogen to plasmin, thanks to TPA, but not only TPA; also, we have urokinase, factors XII, XI, and plasmin, occurring. So, plasminogen to plasmin will convert fibrin into fibrin degradation products, and this same plasmin will convert stabilized fibrin into the D-dimer. Fine. We can inhibit the TPA at this level, and we can inhibit plasmin at this level. Who inhibits TPA at this level? The topic of today's video: plasminogen activator inhibitor. Plasminogen activator is just a fancy term for TPA, because TPA is the plasminogen activator par excellence. So, when you say plasminogen activator inhibitor, it just means TPA inhibitor. Okay, cool. So, we can inhibit it at this level or at this level. Now let's talk about the first plasmin activator inhibitor, which inhibits this process at this freaking level.
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So here's the complete story of fibrinolysis: You have the intrinsic or the extrinsic coagulation pathway; prothrombin to thrombin; fibrin into fibrin. Now we have the clot stabilized, the clot by factor XIII. Now we have stabilized fibrin. Now let's destroy the clot and restore the function and restore the normal blood flow. We need plasmin. But plasmin is present in an inactive precursor form called plasminogen. Nice. We need urokinase and TPA to activate plasminogen to plasmin. Now plasmin will degrade fibrin to fibrin degradation products. It will degrade fibrin, the stabilized one, into the D-dimer. And will degrade fibrinogen into fibrin degradation products. It will also digest factors V and VIII, as well as prothrombin and factor XII. This is just awesome. Think of thrombin and plasmin as enemies. Thrombin wants blood coagulation; plasmin wants to destroy the clot and restore the blood flow. Both are proteases, by the way, which are enzymes that destroy or digest proteins. Thrombin is the hero of coagulation; plasmin is the hero of fibrinolysis, and they are enemies. Nice.
So how does plasmin know that this protein is the fibrin, and it will destroy only the fibrin, meanwhile it doesn't destroy proteins in your muscle, for example? And here is the secret: The secret is in the receptor. It has a receptor; that's how it can tell the difference between fibrin and other proteins in your body. Cool. Recall that when plasmin destroys the fibrin, it produces fibrin degradation products, or FDPs. However, when it breaks down the stabilized, covalently cross-linked fibrin, it produces the D-dimer. How does it know fibrin? Thanks to the lysine binding site, because there is a lysine on the fibrin, as I've told you in my previous videos. There are two types of plasminogen activators: We have the tissue type, or TPA; urokinase type, or UPA. Both of them are plasminogen activators; that's why the topic of today is plasminogen activator inhibitor, which is going to inhibit both of these. And I've talked about the TPA drugs before and their clinical uses and side effects in previous videos. I've also talked about the absolute and relative contraindications to TPA use. That's why you need to subscribe, guys, because fibrinolysis is a very important step; we should regulate it, because power corrupts, and absolute power corrupts absolutely.
We have three regulators: plasminogen activator inhibitors, alpha-2-antiplasmin, and thrombin-activatable fibrinolysis inhibitor. Plasminogen to plasmin, thanks to TPA and urokinase. Who inhibits this step? Plasminogen activator inhibitor 1 & 2. Then we have plasmin. Who inhibits this step? Alpha-2-antiplasmin. Alpha-2-macroglobulin. Plasmin degrades fibrin into fibrin degradation products and the stabilized fibrin into the D-dimer. Who inhibits this step? Thrombin-activatable fibrinolysis inhibitor. Remember when I told you that thrombin and plasmin are enemies? Yes, indeed. So here are the three regulatory mechanisms of fibrinolysis: First, plasminogen activator inhibitor, which inhibits the activators of plasminogen, which are TPA and urokinase, UPA. Alpha-2-antiplasmin inhibits the free plasmin. Any free plasmin will bind to alpha-2-antiplasmin to its demise. Thrombin-activatable fibrinolysis inhibitors, or TAFI, they cleave the N-terminus of fibrin, which will lead to decreased fibrinolysis, because this N-terminus is where plasmin would work. When you cleave the N-terminus, plasmin has nothing to work on; it's like taking the case documents from the lawyer.
So here's the whole story: Plasminogen to plasmin, thanks to thrombin, TPA, or urokinase, etc. Who inhibits this step? Plasminogen activator inhibitor. Nice. Then we have plasmin. Who inhibits it? Alpha-2-antiplasmin. Okay. Relevant. Then we have fibrin degradation products and the stabilized fibrin to D-dimer. Who inhibits this step? Thrombin-activatable fibrinolysis inhibitor. And they need thrombin to be, because it's called thrombin-activatable. Thrombin activates this compound. The two types of plasminogen activator inhibitor are 1 and 2. 1 is secreted by the endothelium as well as adipose tissue; 2 is secreted by the placenta. Therefore, in pregnancy, the amount of PAI-2 is going to increase. Unless interested in facts, I'm more interested in helping patients, so let's go to the clinical pearls. Plasminogen activator inhibitor deficiency will lead to: You have a deficiency of the inhibitor, which means TPA is left free. When TPA is free, it will cause fibrinolysis, clot lysis, which will lead to bleeding; or if you want to be sophisticated in front of your professor, say hemorrhagic diathesis. Was just mainly a bleeding problem. Then we have increased PAI, will lead to increased risk of thrombosis and atherosclerosis. Why increased risk of thrombosis? Think about it: If you have an increased inhibitor, you will have decreased TPA, and you will have decreased fibrinolysis. You are not going to lyse your clot; the clot will persist; you have an increased risk of thrombosis, which makes perfect sense. Cancers, obesity, metabolic syndrome can have increased PAI; that's why these diseases have increased risk of thrombosis and retention. To increase that, the PAI-1, plasminogen activator inhibitor 1, which will lead to increased risk of atherosclerosis, the condition of hard vessels.
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