Transcription
Hey guys, it's Médicos is Perfection Alice, and let's continue talking about bleeding and coagulation disorders. I don't just produce individual videos; I produce playlists, so please subscribe and check my playlist. It's called Bleeding and Coagulation Disorders.
In the previous videos, we have talked about thrombomodulin, alpha-antiplasmin, plasminogen activator inhibitors, D-dimer, and others. So again, please subscribe. Today we'll talk about protein C and protein S. These are vitamin K-dependent factors, and they are really important in stopping coagulation by inactivating factors V and VIII. With that being said, now let's get started. [Music]
As I've told you 17 times before, hemostasis has many steps: basic instruction, temporary plug, coagulation, fibrosis, and regeneration. We've talked about the first four, and now we'll talk about protein C and S—how to inhibit step number three. So before we inhibit step number three, let's first talk about step number three. This is the secondary hemostasis, also known as the clot formation or the thrombus formation. Nice. We have intrinsic and extrinsic pathways. To understand this, let's start from here.
Fibrin is the hero; it's a fibrous protein, and it's formed from fibrinogen, which is a precursor, an inactivated protein. And in order to activate fibrinogen into fibrin, you need thrombin, the protein of the thrombus. Thrombin, again, is present in an inactivated precursor form called prothrombin. To activate prothrombin to thrombin, you need not just one guy; you need a committee, the congressional committee, consisting of two numbers and two words. What are the two numbers? Five and ten. The two words: calcium and phospholipids. To activate this committee, you have the extrinsic pathway when you require something from outside of the blood vessel, or intrinsic from when you require something from within the blood vessel. Extrinsic: what's outside of the blood vessel? That's evidence for trauma; it's called the tissue factor. Because when you have trauma, the tissue is now being connected with the bloodstream. This is evidence of trauma, disturbance of the endothelium and the subendothelial collagen in the basement membrane. So when you have the tissue factor coming in contact with the blood, it's evidence of trauma. Tissue factor activating factor VII to VIIa will activate the congressional committee by activating factor X, which is the most important factor, by the way. That's it for the extrinsic pathway. Now, if you'd like to inhibit the extrinsic pathway, you have tissue factor pathway inhibitor, or TFPI.
Then the intrinsic pathway: what's within the blood vessel? The subendothelial collagen, the basement membrane, the high molecular weight kinin, the plasma kallikrein. Very nice. This will activate factor XII into XIIa. Factor XII will activate factor XI, skipped factor X because factor X is in the middle. Let's go to factor IX and factor VIII. When these are active, this is the cascade. Why do we need the cascade? I've told you before in my video on coagulation cascade. Now X is active into Xa. The committee will work to activate prothrombin to thrombin, fibrinogen into fibrin. Are we done? Not yet. The last factor mentioned, the highest number was 12; let's add factor XIII here to stabilize the fibrin into stabilized fibrin fibers. Who inhibits the intrinsic pathway? You have antithrombin III, antithrombin to inhibit the thrombin as well as IX, X, XI, XII. Protein C and S, the topic of today's video, will inhibit factors V and VIII. Factors V and VIII are part of the coagulation factors; in other words, factor V and VIII are procoagulation. Protein C and S, by definition, are anticoagulation; they want you to bleed.
Talked about thrombomodulin in the previous video, which was amazing; you must watch it. Thrombin plus thrombomodulin will have the thrombin-thrombomodulin complex. Thrombomodulin is going to modulate thrombin from being procoagulation into being anticoagulation. So after forming this complex, will activate protein S. Then protein S comes before C; I don't care about the alphabet right now. And then C will inactivate factors V and VIII. Those are procoagulation; when you inactivate them, you're anticoagulation. When you are walking down the street and you meet a medical student, ask them one question: What are the vitamin K-dependent factors? And they will say, "Okay, they are II, VII, how do we write VII? VII, IX, and X, prothrombin, VII, IX, X." That's it. That's what most students will tell you, but they will forget about protein C as well as protein S. So now whenever your professor asks you, please mention the vitamin K-dependent factors; you have II, VII, IX, X, protein C, and protein S. Don't ever forget protein C and protein S.
So protein C and protein S, they are vitamin K-dependent factors; they are produced by the liver. What's the process? It's called gamma carboxylation. What's the name of the enzyme involved in gamma carboxylation? Let me know down below in the comments. Thrombin now will activate protein C. To activate protein C, you need protein S as well as thrombomodulin as well as endothelial protein C receptor, EPCR. So now protein C is active; we call it activated protein C, or APC. This is very important. The activated protein C will inactivate the coagulation factors V and VIII. So if V and VIII are accelerators to coagulation, protein C is a brake on coagulation. So the mnemonic is: protein S, protein C suppress coagulation. Accelerators of coagulation: Z's, brakes of coagulation. The accelerators include thrombin as well as all of the coagulation factors, including factors V and VIII. The brakes include the anticoagulant coding from emulsion and even protein C and S.
So please choose the correct answer: Patients who have a deficiency of protein C or protein S may suffer from bleeding or thrombosis. Please pause, and the answer is B: thrombosis. Protein C or activated protein C is the break, the break of coagulation. When you don't have a break, you have lots of accelerators of coagulation. When you have lots of coagulation, you thrombose. If you didn't answer that question correctly, maybe you suffered from congenital hypothyroidism when you were a baby. I'm not making fun of patients; I'm only making fun of you.
Question number two: Patients who have familial thrombophilia were found to have a resistance to PC, be more sensitivity to APC. Now please pause, and the answer is A: resistance to APC. Now let me explain. Familial thrombophilia means love; they are lovers of thrombosis; they adore thrombosis. So they have lots of thrombosis going on. Okay, if you have lots of thrombosis going on, you are using the accelerators a lot; you are not using the brakes, probably. You have a resistance to the brakes, resistance to the activated protein C. If you didn't answer this question correctly, chances are you have an extra chromosome. There is no shame in seeking help.
Question number three: Factor V Leiden is a genetic disorder. Patients have a mutant factor V, which is resistant to inactivation by the activated protein C. This makes them more liable to bleeding or thrombosis. Now pause, and the answer here is B: thrombosis. Factor V is not going to be inactivated; it's mutant, and it's resistant; it's the son of a gun; it's not going to be inactivated. So when you have the accelerator that's cannot be overridden by the brakes, now the brakes are useless. We have lots of acceleration; you have lots of thrombosis. If you don't answer that question correctly, maybe you suffered from folate deficiency back in the days when you were in the womb. Oh, you're making fun of patients? No. First of all, I'm not making fun of patients; I've said it before many times. I'm only making fun of medical students who cannot answer the questions. Okay, clinical pearl: Did you know that infusion of protein C can ameliorate or mitigate sepsis, meaning decrease the symptoms of sepsis? Really, protein C will decrease? Yep. Drugs for that? Oh, the emitter in a drug, man, is called what? What's that? Drotrecogin alfa. Drotrecogin, baby. Who named these things?
Next: warfarin-induced skin necrosis. First of all, why? Because warfarin inhibits the vitamin K-dependent factors, which are protein C, protein S, factors II, VII, IX, X. However, warfarin inhibits protein C and S, the brakes, before it inhibits factors II, VII, IX, and X, the accelerators. When you inhibit the brakes before the accelerator, you'll have more acceleration first, which will lead to more coagulation. When you have more coagulation, you have more clots; they will occlude the vessel, leading to tissue hypoxia, and now the skin cells will die. Is it cell homicide or suicide? It's homicide; it's skin necrosis because suicide is any apoptosis. If you already have protein C or protein S deficiency, you are more liable to skin necrosis if you take warfarin. Think about it: if you have a genetic problem that affects your brakes, you're already having loose brakes because you're not changing the pads or the rotors or the calipers; your brakes suck. Now you are taking warfarin to inhibit the brakes. Are we going to have any brakes at all? No. When there are no brakes, what's left? The accelerators of what? Of coagulation. You will have lots of thrombosis, leading to lots of skin necrosis. So if there is a patient with protein C and S deficiency, please don't put them on warfarin. What if I don't have any other drugs but warfarin? Use low-dose warfarin. If you have other anticoagulants, please go for it.
Now, quiz time for my heroes: What's the difference among protein C, C-reactive protein, and C-peptide? Let me know down below in the comments. And by the way, I've made a video about C-reactive protein before; it's in my playlist about Rheumatology. Thank you so much, guys, for watching. Please subscribe and hit the bell. Follow me on Facebook and Instagram. Get all of my notes and all of my hematology cases by going to patreon.com/médicos. Be safe, stay happy, and study hard. This is Médicos is Perfection, where medicine makes perfect sense.