Transcription
Hey guys, it's Medicosis Perfectionalis, where medicine makes perfect sense. In the previous video, we had an introduction about secondary hemostasis or coagulation. Today, let's talk about the coagulation cascade, the coagulation factors that come from the liver. Indeed, they are beta globulins, and let's get started. [Music]
If you haven't watched my previous videos, it means you live under a rock, literally. These videos are amazing. Please subscribe and save this playlist: Hemostasis—prevention of blood loss by stopping bleeding. Steps: vasal constriction, temporary platelet plug (which is primary hemostasis thanks to platelets), coagulation (which is called secondary hemostasis thanks to coagulation factors), fibrinolysis to dissolve the clot, restore function, and restore the blood flow, and then regeneration. Primary hemostasis is balanced on the dynamic harmonious antagonism between the smooth endothelium (which wants the blood to flow) and thrombocytes (which favor thrombosis).
Here is the entire story: injury, vasal constriction, temporary platelet plug. Depending on the type of trauma, if it's very small, the platelet plug is sufficient; if it's larger, we need secondary hemostasis, also as coagulation, also known as the fibrin meshwork to trap the red cell. Then, the clot contracts, producing serum, and then fibrinolysis to destroy the clot and restore blood flow and regenerate.
Here is the process of vasoconstriction. I've explained it in a previous video. We start with a trauma, then back pressure; these muscles contract, constricting the vessel. The vessel by itself constricts; it's a local myogenic spasm. Thromboxane A2 helps the pro-constriction. Substances include serotonin, thromboxane A2, epinephrine, and fibrinopeptide B. The platelet is like the policeman inspecting the gate—by the gate, I mean the endothelium. If everything is nice and secure, okay, it's calm, it's a quiet night, everything is fine. But if the gate is open and the layer underneath the gate, called subendothelial collagen, is exposed, the platelets go mad. Same thing with this amazing engineer; he just goes bananas when he sees a cracked wall because it could be something major.
Steps of primary hemostasis: platelet adhesion thanks to GP 1B and the von Willebrand factor (where does the von Willebrand factor come from? From the platelet and the endothelium). Then comes platelet activation; they activate, swell, contract, and release the granules. ADP—ADP-dependent expression of GP2b3a receptors—and it's a whistleblower; it whistles for other platelets to come to help. Platelet aggregation—thromboxane A2, which is an even bigger whistleblower. Platelet aggregation promotes vasoconstriction and bronchoconstriction. Then platelet aggregation—this platelet and this platelet will connect together; each one has its own GP2b3a receptor; fibrin molecules form in between. Then primary hemostasis is done. Secondary hemostasis is to do this: the fibrin meshwork. Then the fibrin meshwork traps the red blood cell, forming an even bigger and better plug.
Let me explain the coagulation cascade like your crazy professor. You will never understand the thing, but then I'll explain. Okay, so coagulation is: we have the intrinsic pathway. The intrinsic pathway has Factor 12; then it's converted into 12a; then 11 converted into 11a; then after this, we have… um… 10? No, no, no, no, it's not 10; it's I believe it's nine and to 9a. Then after nine, we have like Factor 8, which is activated; then this will activate Factor 10, and then we have Factor 10a. This is the intrinsic pathway. Also, there is another pathway called the extrinsic pathway, and here we have only one factor; it's called Factor 7. Factor 7 is converted into 7a, and then they will activate Factor 10. Factor 10, together with Factor 5a and some calcium, let's add some membrane phospholipid; they will help the prothrombin being activated from prothrombin into thrombin; and then thrombin will activate… by the way, prothrombin is Factor 2… thrombin helps activate fibrinogen into fibrin, and for some reason, we call fibrin Factor 1. And then fibrin will have Factor 13 to stabilize the fibrin into stronger, better fibers. And this is the story of coagulation. Go to hell. Did you understand the thing? No? Now let's do it the Medicosis way.
So let's start with this nice scientist, Morawitz, in 1910. He said that the clot is just the fibrin fibers, okay, and this fibrin is present in a precursor form called fibrinogen. That's—I called it fibrinogen. Why? Gen means genesis. This fibrinogen will cause genesis of fibrin. Brilliant. What does fibrin mean? Fibrin means protein, and fibrin because it's a protein of fibers. Excellent. Then, to stimulate fibrinogen and convert it into the active fibrin, you need something called protein of thrombus. Let's call it protein thrombus. So we have thrombin. This thrombin is present in a precursor, inactivated form called prothrombin. Pro means pre; it's pre-thrombin; it will form thrombin. Since this was the first factor to be discovered and the factor that leads to the real clot, which is the fibrin, let's call it Factor 1. What's before it is prothrombin; let's call it Factor 2. Very interesting. After the great scientist Morawitz, we have the modern coagulation theory. We just discovered some reactions here before and some one reaction here after fibrin. So that's basically it; we have these same two steps: a cascade before fibrin and a stabilizing factor after. Okay, so the cascade will explain this: what the flip is fibrin stabilizing factor? It was—it—we discovered it by chance. Some patients formed fibrin fibers, and they trapped the red blood cells, and their bleeding stopped. Excellent. Then, suddenly, out of the blue, this fibrin meshwork was destroyed, and the patient bled to death. What the what? Yes, because these fibrin fibers were unstable. You need something to stabilize the fibrin into stable, stronger fibrin fibers that are irreversible; you cannot break it down easily. This is called fibrin stabilizing factor. Since we discovered all the other factors from 3 to 12, because, as you know, this is one and this is two, so 3 to 12, let's call the fibrin stabilizing factor Factor 13. That's brilliant.
Then let's talk about Factors 3 to 12. We have two pathways: the intrinsic and the extrinsic. This pathway is called the common pathway. A cascade is a small waterfall; each step is stronger than the preceding one: boom, boom, boom, boom, boom, boom, boom, boom. It allows time and steps for regulation; it's not all or none; you can regulate it if it has several steps. And if it had several steps, it means that every step is going to be stronger than the one before it. This is how you form strong fibrin fibers and stop the bleeding efficiently. That's why secondary hemostasis is way, way, way more important and more efficient than the stupid platelet plug of primary hemostasis because the platelet didn't have a cascade. So here is the story: you injure yourself, vasoconstriction, platelet plug (also known as primary hemostasis); if it's—it's very weak and it's temporary. Then comes the coagulation cascade: boom, boom, boom, boom, boom, boom. Prothrombin, thrombin, fibrin, strong fibrin, trap the red cells, boom, we're done. And then stabilize it with Factor 13. That's why we need a cascade; every step is stronger than the one before it. Unless there is platelet activation in vain, there is blood coagulation. There is no platelet activation; you cannot form blood coagulation. There are only two ways to coagulate, but there are tens of ways to bleed. Oh my goodness, this is deep. What are the two ways to coagulate? You have the intrinsic pathway and the extrinsic pathway—two ways to coagulate. This is physiology. Ten ways to bleed—this is pathology. Here we have intrinsic and extrinsic pathways. What? Why do we call it intrinsic? Intrinsic to the blood; it's intrinsic to the blood vessel; something from within will start the ignition—self-sufficient. We depend on factors from within the blood, or at least the blood vessel. How about you? Extrinsic? No, I need something from outside the blood. You mean like the tissue? Yeah, that works. We are dependent on outside factors; we are not self-sufficient. So the extrinsic pathway depends on factors from outside the blood; that's why we call it extrinsic. Intrinsic has more steps; it's a longer cascade. If it's a longer cascade, it's going to be stronger; that's the whole point of a cascade: boom, boom, boom, boom, boom, boom, boom. It's called acceleration; it's going to be more efficient. Yeah, it's a longer cascade. Extrinsic—less steps, shorter cascade; therefore, it's faster, but less efficient.
Here is a question for you: when you put blood in a test tube (except for the purple one), it coagulates using which pathway? Is it the intrinsic pathway, the extrinsic pathway, or both? I'll give you 3 seconds. Go. And the answer is the intrinsic pathway because remember the extrinsic wants something from outside the blood, for example, the tissue. But when you put blood in a test tube, you don't have tissue; it has to be the intrinsic pathway. Use your prefrontal cortex, for heaven's sake.
So here's the old theory: fibrin is the clot; comes from fibrinogen. Then we have thrombin; comes from prothrombin. What activates prothrombin into thrombin is the prothrombinase complex. What's the complex? It has four members; I call it the famous quad. Quad is like triad, but for four: calcium, membrane phospholipid, Factor 5, and Factor 10. Which one is the most important? Factor 10, baby. This is the best. 10 is a very important number; that's why the gurus on the internet will write blogs about the 10 ways to lose weight, the 10 ways to travel abroad, the best 10 places to visit in blank. Here's a quick mnemonic for you: here's fibrin, and here's fibrinogen. This is the president. Okay, will you leave the president alone to rule the country? No. This is called dictatorship, like the country that I came from. Power corrupts, and absolute power corrupts absolutely. We need checks and balances. Let's add a vice president: prothrombin, Factor 2. But we need more; we need a congressional committee: Factors 10, 5, calcium, and phospholipid to form the prothrombinase complex. The president cannot act alone without approval of Congress first.
Let's start with the extrinsic pathway. We start from here because this is how history worked: fibrin—this is the clot; it's what Galen and Hippocrates said. Then we have fibrinogen, then we have thrombin (the protein of thrombosis), and then prothrombin. Prothrombin is going to be activated into thrombin, which will convert fibrinogen into fibrin. Fibrin traps the red blood cells. What converts prothrombin into thrombin? Prothrombinase complex—the quad, the committee; it has 10, 5, calcium, and phospholipid. Don't ever forget that. What is the extrinsic pathway? Extrinsic pathway, can you… um… tell us your story? Of course. I'm extrinsic, which means I need something from outside of me—from outside of the blood and the blood vessel—even tissue. Yeah, the tissue works fine. Why do you need something from the outside? I'll tell you, my friend, because what's the evidence that you are bleeding and you need coagulation? How is the tissue an evidence? Think, think. If there is a trauma, and here's the tissue, and here's the blood vessel, the only way by which this tissue is going to be in contact with the blood directly is only when you have a trauma; you have pierced through the tissue and this vessel wall and the endothelium, and now the blood is going to be in contact with the tissue factor, which means there has to be a trauma, which means let's work in order to form a clot. Brilliant. So what factor are you looking for? It's called the tissue factor—the factor from the tissue. It's—it's—it can't be easier; it's—it's very easy. Tissue factor; we call it tissue thromboplastin. I mean, look at the name: in means protein, plast means creation, thrombo means thrombosis; it's the protein that creates the thrombus. Wonderful. Or tissue phospholipid; it comes from the tissue phospholipid; so we call it TPL. Okay, so let's do it again: we have a trauma; the tissue factor comes in contact with the blood; the blood has Factor 7; yes, indeed. When tissue factor comes in contact with Factor 7, it means that there's a trauma; then Factor 7 is going to activate into Factor 7a (a for active); then it's going to activate the famous Factor 10, the hero, into 10a. 10a, together with 5, phospholipid, and calcium, is going to form a prothrombinase complex. Prothrombinase will convert the prothrombin into thrombin, converting the fibrinogen into fibrin; trap the red cells, boom, we're done. Extrinsic pathway is done; it's fast, but it's less efficient. As the extrinsic pathway is starting to work, the intrinsic is also working, but it takes longer because we have more steps and more cascade—longer cascade.
So intrinsic pathway, please tell us your whole story in detail. I'm intrinsic, so I need something from within us. By that, you mean… I mean something from within the blood vessel. Will the subendothelial collagen work? Yeah, it's part of the dead gum basement membrane; it's part of the blood vessel; it works. So when you injure your tissue, the subendothelial collagen is exposed. So—so this is an evidence that there is a trauma; it's an evidence that you are bleeding; it's evidence enough for me in order to work and start the cascade in order to form fibrin meshwork to stop this bleeding. Wonderful. So please work. I start with Factor 12, then Factor 11, then after this I have Factor 9, then I have Factor 8. Why do we call them these names? Because we discovered them like from here to here; we discovered Factor 7 for the extrinsic and another factor for the intrinsic; we called it Factor 8. Then we discovered more factors; we have nine, so we have 8, 9, 10 is here, so skip 10, 11, 12. 8, 9, 11, 12. Let's do the whole intrinsic pathway: we have subendothelial collagen exposed, activate 12, then activates 11, skip 10, activate 9, and have the 8. Von Willebrand factor is part of Factor 8; this is important; this will activate Factor 10 into 10a. And 10 is the hero, together with calcium, phospholipid, and Factor 5; we have two factors and two substances, or you can say two numbers and two words. Then we have the—the prothrombinase complex, the quad, the committee, to convert prothrombin into thrombin, to convert fibrinogen into fibrin; fibrin traps the red blood cells, boom, we have a clot, baby.
So let me tell you the whole story: you injure yourself; the platelets start to work; then comes the coagulation cascade. We start with the extrinsic—the tissue factor, which is in the tissue, came in contact with the blood, which is in the vessel—i.e., there is a trauma; it's very easy, like it's self-evident; there's a trauma, fine. Tissue factor activates Factor 7 into 7a, converting 10 into 10a. At the same time, the intrinsic is working like mad, but it takes time because it's a longer cascade; however, it's more efficient; it's more—has more steps. We start with the subendothelial collagen; then you have two factors after 10 and two factors before 10. Let's activate 10 into 10a. Von Willebrand factor, which came from the platelet and the endothelium, is part of Factor 10. Okay, 10, 10a, together with 5; we have two numbers and two words. Prothrombinase complex: prothrombin into thrombin, fibrinogen into fibrin. But we need to stabilize this fibrin by another factor. Since we are done with these factors, the last name was 12; let's call it Factor 13, the fibrin stabilizing factor. It converts the fibrin from being labile to a more stable fibrin; this is called crosslinking. This, my friends, is why we need a cascade: boom, boom, boom, boom, boom, boom, boom. Fibrin. Let's have some fun. Remember the most important factor? Yes, Factor 10, in the common pathway, standing in between the intrinsic and extrinsic pathway. So here is Lionel Messi, and here we have the four factors. Why four factors? Because we have two factors before 10 (8, 9), then we have 11, 12. All of these are part of the intrinsic pathway. When 10 is in the middle, everybody is surrounding him to protect him because he is a public figure. One of Medo's fans commented on one of my videos; he said, "If I had a million YouTube accounts, you would have a million subscribers." Thank you, dear. His name is IHateRonaldo. Okay, I'm old school, so I assume this is his real name because who am I to judge? Why would anybody hide his identity on the internet? Thank you, my friend, and this video is just for you. Enjoy.
So let's do it from scratch. Okay, we start from here. What's the clot? The clot is fibrin. So let's do fibrin. Then the fibrin comes from fibrinogen. Fibrinogen is also known as Factor 1 because it's the factor just before the fibrin. From fibrinogen to fibrin, we need the protein of thrombosis—the famous thrombin, protein of thrombin—to activate fibrinogen into active fibrin. Prothrombin comes from prothrombin, which is pre-thrombin. Prothrombin is inactive; thrombin is active. This is called Factor 2. Very nice. Here we have the prothrombinase complex, also known as prothrombin activating complex; it has four members. Who's the most important guy? Messi—10. And we have also 5; those are two numbers; we need two words: calcium, baby. Not just calcium; charged calcium, ionized calcium, because the only form of active calcium in your body is the ionized one. No one has ever had tetany because of the non-ionized calcium; it's always the ionized because it's the one that's active. The non-ionized calcium is garbage; just put it in some bone, give you some like kind of a matrix or something strong, give it a context, and that's it. But the physiologically active one that makes symptoms such as muscle contraction or blood coagulation is the active, charged calcium. The fourth member is the membrane phospholipid, or some phospholipids. So in order to activate 10 into 10a, we need two pathways. Let's start with the extrinsic pathway. Extrinsic pathway: I need something from the tissue—from the extrinsic—something from outside of me; it's called the tissue factor; it's also known as tissue thromboplastin. This will activate the only factor that we have here, which is Factor 7, into Factor 7a. 7a will convert 10 into 10a. We're done with the extrinsic pathway. Very well done. Let's go to the craziest one: intrinsic pathway. Intrinsic pathway: we have two before 10 and two after 10 because 10 is Messi—is the most important public figure; we need to protect it; put two guards in front, two guards in the back. Let's start: 8 and 9 before Messi, and 11, 12 after Messi. So we have 12 into 12a, 11 into 11a, and you know all of this garbage. What activates Factor 12? Yes, indeed, the subendothelial collagen—something from within the vessel. Now pause the video, bring a sheet of paper, and try to do it yourself; you will never forget it forever. Let's have some mnemonic time. As you know, fibrinogen is the president; prothrombin is the vice president; that's why this is Factor 1 and this is Factor 2. Here we have the congressional committee, and here we have the intrinsic, which is the Senate. Why are the senators old? The intrinsic pathway is very slow; it takes time to grow gray hair. Okay, it's slow, but they are more efficient; they are old, and they have experience. Then the House of Representatives—those are young guys. Okay, just young kids; they are fast; they don't know what they are talking about; however, they are less efficient, why? Because they are young, and it's a shorter cascade. What's the most important factor? 10. And this is how you teach coagulation cascade. Let's do it for the last time: here we have the extrinsic pathway; the extrinsic pathway has two before 10, two after 10: boom, 10, 10a, and we are done; the rest is history. The extrinsic pathway—the shorter one—only has 7. So let's have some fun. Okay, everything here is two letters. This extrinsic pathway needs the tissue factor (two letters), and we measure it using the PT test (prothrombin time), and the drug that inhibits this pathway is warfarin (actually warfarin inhibits both pathways, but it's better measured by the PT test). Nice. Let's go to the intrinsic pathway—the longer one. Everything here is three letters. It's activated by the subendothelial collagen. The test for it is the PTT (partial thromboplastin time), and heparin inhibits this pathway (actually heparin can inhibit more than this pathway, but it's better measured by the PTT). From here to here is called the common pathway. And if you are confused between PTT and PT, just remember: PT has two letters; it has to be the shorter pathway, which is the extrinsic one. PTT has longer letters; some people write it like this: aPTT; it has to be the longer pathway.
Quiz time: I've told you that blood coagulates in vitro (which means in the test tube) via the intrinsic pathway, but how come? How is that possible since there is no subendothelial collagen in the test tube? How are you going to coagulate using the intrinsic pathway? Let me know in the comment section.
In the next video, we'll talk about fibrinolysis and the tissue plasminogen activator, which destroys the clot and restores function. Thank you for watching. Don't forget to subscribe; support this channel on Patreon to get all of my notes. Thanks for watching, and as always, be safe, stay happy, and study hard. Medicosis Perfectionalis.