Transcription
It's Medicosis Perfectionalis. Resuming our lectures on bleeding and coagulation disorders. We have talked about primary hemostasis and secondary hemostasis. Today, let's talk about high molecular weight kininogen, which produces bradykinin and activates Factor XII into Factor XIIa. So let's get started. [Music]
As you know, hemostasis is prevention of blood loss. It has many steps: vascular constriction, then temporary platelet plug (also known as primary hemostasis), then coagulation cascade (also as secondary hemostasis), then fibrinolysis. You injure yourself because you're foolish. Vasoconstriction occurs, which is the first step. Then, temporary platelet plug; this is called primary hemostasis. Depending on the type of injury, if it's very small, the primary hemostasis is very sufficient. If it's larger, we need something more: the coagulation cascade (also known as secondary hemostasis) to lay down its fibrin meshwork, trapping the red blood cells. Then, the clot contracts, producing serum. Fibrinolysis occurs to restore blood flow and then regenerate the tissue.
First step: vascular constriction, which is a local myogenic spasm. Remember, there are only two ways to coagulate, but there are several ways to bleed. What are the two ways to coagulate? The intrinsic pathway and the extrinsic pathway. Here is our intrinsic coagulation pathway. Who is the hero of coagulation? Factor X. It activates prothrombin. In the intrinsic pathway, we have two factors before X (VIII and IX) and two after X (XI and XII). XI and XII happen to be called the contact group. Why contact? Because they are activated with contact with the subendothelial collagen in the basement membrane.
Coagulation cascade is best explained from the bottom. Fibrin is the meshwork; fibrinogen is the precursor to fibrin. Then, we have thrombin, present in a precursor, inactive form called prothrombin. So, prothrombin, thrombin, fibrinogen, and fibrin—boom, we are done. This is the president; that's why we call it Factor I. This is the vice president that breaks the tie; we call it Factor II. Then, we have the prothrombinase complex; we have a committee, a congressional committee of four members: two numbers and two words. What are the two numbers? Five and X. Which one is more important? Of course, X. What are the two words? Calcium and phospholipids. Cool, or not two letters, but two words. Fine.
We have the extrinsic pathway, which is faster, such as the House of Representatives. They are young folks; they don't know what they're talking about. And then there is the more elegant and wiser Senate, which takes time; it's very slow but more efficient. Extrinsic pathway is activated by the tissue factor. When the tissue factor comes in contact with the blood, it's evidence of trauma. So, we have the tissue thromboplastin (which is the same thing as tissue factor), activating the only factor that we have in the extrinsic pathway: Factor VII into the active form of Factor VII, which will activate Factor X into the active form of Factor X. The committee is working, agreeing on the decision of coagulation: prothrombin, thrombin, fibrinogen, fibrin—boom, we are done.
The intrinsic pathway, on the other hand, is longer. It starts with Factor XII, one of the contact group. Why contact? It has to come in contact with the subendothelial collagen in the basement membrane of the blood vessel, which means there is trauma, of course. When it comes in contact, now XII is active, XI is active; skip X because X is the most important here in the common pathway. Then, we have IX and we have VIII. Remember, von Willebrand factor is part of Factor VIII. Von Willebrand factor (or as Germans say, von Willebrand factor) is part of the coagulation cascade and part of the primary hemostasis because, if you remember, platelets need something to adhere to; this something is called the von Willebrand factor. We have missed something: the fibrin stabilizing factor. We're done with here. Here, the biggest number was XII; let's call it number XIII. Factor XIII stabilizes the fibrin into more stable fibrin by crosslinking the fibrin fibers. If you can see and you have good visual acuity, you can see that calcium is involved in many steps; that's why calcium is coagulation's quick comparison between the intrinsic and the extrinsic pathway. Intrinsic means we need something intrinsic to the blood, something from within—#self-sufficient. What's this something from within? Our famous blood vessel wall, also known as subendothelial collagen. The extrinsic pathway needs something from outside, called tissue. So, the tissue factor (also known as tissue thromboplastin, also known as tissue phospholipid).
Intrinsic pathway has more steps, a longer cascade. If it's a longer cascade, it's more sufficient; it gains gravity and momentum as it goes downwards. It starts with Factor XII. The extrinsic pathway is shorter and starts; it only has Factor VII. Faster, but less efficient. What activates the intrinsic pathway? What is the subendothelial collagen? What else? The platelets. What part of the platelet? The platelet factor 3. What else? The great high molecular weight kininogen, which is the topic of today's video. Cool factors here. Here are only seven factors; here are XII, XI, skip X because X is the most important guy, IX, and VIII. Cool. PT measures the extrinsic pathway and the common pathway. What is PT? Prothrombin time. PT measures the extrinsic and the common pathway. What the flip is PTT? Partial thromboplastin time. So, here is your famous intrinsic pathway: XII, XI, skip X, IX, VIII, activate Factor X, and boom, the intrinsic pathway is also known as the contact activation pathway because it starts with the contact group; they have to come in contact with the basement membrane, specifically the subendothelial collagen; that's why we call them the contact group. What else stimulates them? The platelet factor 3 and the great high molecular weight kininogen. High molecular weight kininogen activates Factor XII into XIIa and XI into XIa. Thank you so much. Also, we have plasmin. Plasmin activates only Factor XII. Cool. High molecular weight kininogen. Thanks to kallikrein, it's converted into bradykinin, the great pro-inflammatory guy that will have many functions, such as vasodilation, also pain. This is not the end of the video yet, but I have 50 hematology cases on my Patreon website. You can't mess those up. Go to patreon.com; enjoy these cases, and I guarantee you you will never answer all of them correctly. Take it to the freaking bank. Factor XII into XIIa, XI into XIa. Then, we complete the intrinsic coagulation cascade. High molecular weight kininogen is converted into bradykinin thanks to plasma kallikrein. Plasma kallikrein activates Factor XII, which returns the favor by activating prekallikrein, which is a precursor form of kallikrein. So, this is one of the few examples of positive feedback loops in your body because most of what you have in your body is negative feedback. Positive feedback is kind of uncommon, but this is a classic example of it. Kallikrein activates Factor XII; Factor XII activates prekallikrein, which is going to be converted into kallikrein in a positive feedback loop. Excellent. What else? High molecular weight kininogen will activate both Factor XII and Factor XI. Prekallikrein is converted into kallikrein, causing high molecular weight kininogen to be converted into bradykinin. High molecular weight kininogen: is it active? Yeah, it activates Factor XII; it produces bradykinin. If it's active, it's a protein. Period. Take it to the freaking bank. It's a plasma protein. What kind of plasma protein? It's a globulin. Is it alpha, beta, or gamma globulin? It's an alpha globulin, not to be confused with the coagulation factors, which are beta globulins, not to be confused with your immunoglobulins, also known as antibodies, which are gamma globulins. This high molecular weight kininogen, which is inactive, is activated when it comes in contact with the basement membrane, the subendothelial collagen. It produces bradykinin, which is one of the kinins. "Kin" means protein, and "k" from kinetic means to set in motion. High molecular weight, sorry, low molecular weight kinin is in the tissue; high molecular weight kinin is in the plasma. Huge difference. High molecular weight in plasma, low molecular weight in the tissue. What the flip does bradykinin do with its life? It contracts the nonvascular smooth muscles, such as the bronchi, causing bronchoconstriction; that's why you end up with dry cough. Why not productive? I'm just constricting the bronchioles; I'm not secreting mucus, so it's not a productive cough; it's just a dry cough. Increase vessel permeability, and this increase of vessel permeability will lead to something called angioedema, which is a medical emergency. Angio means vessel; edema means edema, like accumulation of fluid in the interstitial space. Cool. What else? Pain: acute pain, like when you hit your little toe on the sofa; no chronic pain due to chronic inflammation. I'm increasing vessel permeability; I'm all about inflammation. Vasodilation will lead to hypotension; also, edema will lead to hypotension. So, bradykinin leads to pain, hypotension, dry cough, etc. Let me answer the question from the previous video. I've told you that blood coagulates in vitro via the intrinsic pathway, but how come it coagulates using the intrinsic pathway when there is no subendothelial collagen in the freaking test tube, outside of your body, or in vitro? Yes, it's true that I don't have subendothelial collagen in the test tube; however, I still have high molecular weight kininogen; I still have the glorious plasma kallikrein; and I have the platelet factor 3 and the wettable surface of the glass, which has a negative charge. All of these can activate Factor XII into XIIa; let me start the intrinsic pathway, please, and coagulate your blood. That's why we call the intrinsic pathway the contact activation pathway because it comes in contact with the subendothelial collagen in vivo or the wettable surface of the glass in vitro.
Clinical take-home point: deficiency of high molecular weight kininogen is not clinically significant; it does not cause bleeding. Also, deficiency of prekallikrein does not cause bleeding; it's not clinically significant. Do you know why? Let me know the answer in the comment. If you can get the answer, you are really brilliant, and you understood this video, and my work is done. In the next video, we'll talk about the kallikrein-kinin system and why you get dry cough and edema when you take ACE inhibitors, such as enalapril, lisinopril, etc. What the flip? PR. Thank you for watching. Subscribe to my YouTube channel, follow me on Facebook and Instagram, get all of my notes and the 50 hematology cases and counting by going to Patreon, and I'll give you my bloody Dropbox link. Thank you so much, guys, for watching. As always, be safe, stay happy, and study hard. This is Medicosis Perfectionalis, where medicine makes perfect sense, as long as you go to Patreon.