Alright Ninja Nerds, in this video we're going to talk about hemostasis. First off, what is hemostasis? Hemostasis, well first off we can kind of break apart this term here.
Hemo is blood, stasis means stop, so it's a localized blood stoppage, right? So that's what we're trying to do. Usually this occurs whenever there's some type of damage to our blood vessels, right?
Whenever they're either ruptured or lacerated and blood is actually leaking out. And our desire is to be able to stop that from happening. So there's a sequence of five steps that we're going to go over throughout this entire length of the blood vessel in order to understand how this hemostasis is occurring.
Before we do that, we really need to understand what is keeping the blood naturally thin? What's keeping it from coagulating on its own naturally? So now we need to go over that before we go into understanding how this coagulation how these actual platelet plug formations and all that stuff is occurring.
So let's come over here and let's understand exactly how the blood is keeping itself naturally thin and preventing it from becoming thrombotic. In other words, trying to form a clot. Our first thing, we have here our endothelial cells, right? So here's our endothelial cells here. We have underneath it our subendothelial layer.
And you know the subendothelial layer is made up of connective tissue, specifically collagen. It's rich and rich in collagen. And then down here we have some smooth muscle cells with some specific types of receptors.
And then over here, these orange cells are gonna be our nociceptors, our pain receptors, right? All right, so first thing, our endothelial cells, they secrete chemicals, two really important chemicals. One is called nitric oxide. And the other chemical that it secretes also is going to be PGI2, which is prostacyclin.
All right, so it secretes these two chemicals, prostacyclin and nitric oxide. What is the purpose of these chemicals? Well, you know, if inside of our blood we have two things, plasma and cells, our formed elements, right?
And those formed elements are platelets, when we're going to care about white blood cells and red blood cells. So circulating through this area, what are we going to have? We're going to have...
These little tiny and microscopic cytoplasmic fragments which are called platelets. And what happens is this nitric oxide and PGI-2, it naturally inhibits the platelet and keeps the platelet inactive and prevents the platelet from being able to bind on to the endothelial lining. That's what it's naturally doing. So what is this whole purpose of this?
It's inactivating the platelet. Okay, so you can think about these platelets as though they're sleeping. Right?
So they're sleeping. They're catching some Z's over here, right? So again, that's the whole purpose of this nitric oxide prostacyclin and activate the platelet and prevent the platelet from binding onto the surface That's one thing to prevent the blood from clotting naturally unnaturally, right? Next thing there's another protein that's present on the membrane.
Actually, it's not a protein. It's a proteoglycan or glycosaminoglycan It should be more specific. It's a glycosaminoglycan and this glycosaminoglycan is called heparin Heparin sulfate.
It's called heparin sulfate. And heparin sulfate is a natural anticoagulant, right? So here's our heparin.
Heparin sulfate. And what does heparin sulfate do? Heparin sulfate binds another protein, which is called antithrombin 3. This is called antithrombin 3, not angiotensin 3, antithrombin 3. Okay, so again, heparin sulfate is bound to the plasma membrane.
It activates antithrombin 3. And imagine antithrombin 3 having like a specific type of hand out here. Imagine it having like a specific type of cutter. Look at this, it's got a little cutter here, a little like blade or radula. And there's specific clotting factors that are constantly circulating throughout your bloodstream naturally. What are those clotting factors that this one degrades?
It degrades clotting factor 2. It also degrades clotting factor 9. And clotting factor 10. So imagine these guys running through this little grinder. What does it do? It inactivates these proteins. So what proteins are inactivated then? You inactivate two, so two is inactivated.
All right, nine is inactivated, and ten is inactivated. So now these guys are inactive. All right, one more mechanism.
This one right here, look at this protein right here. This protein right here is called thrombomodulin. This protein is called thrombomodulin.
So what is thrombomodulin? What does thrombomodulin do? Thrombomodulin binds another protein, and this protein is called thrombin.
Or we can also call it factor 2, right? So you can also call it factor 2. And then what does thrombin do? Imagine thrombin having its hand out here. So imagine it has a hand, right?
And what it does is there's a protein that's kind of circulating by in this area and just so happens to run into this guy. So look at this protein right here. This protein, this green protein, is called protein C. And what happens is when protein C moves across the thrombin, it becomes active.
So now we have activated protein C. And then what does protein C do? Protein C degrades. So again, what is this protein? Protein.
C. Protein C degrades two factors. One is going to be factor 5 and the other one is factor 8. Okay, so these guys are going to be degraded or inhibited. So these are kept inactive. Okay, so again, what happens with these guys?
These are all the three natural mechanisms that are trying to be able to keep the blood naturally thin and preventing it from undesirable clotting. Now that we know that, let's go into the first mechanism. So now...
Well first off, let's actually number them real quickly. What are the five mechanisms right here? We're going to go one is the first one we're going to go into is called vascular spasm.
The second mechanism is called platelet plug formation. And the third is going to be the bear of it all, which is coagulation. This is a beast.
And then the fourth one is clot retraction and repair. And then we'll finish up with fibrinolysis. These are the five steps of hemostasis. And that's what we're going to go into in specific order.
So first one we have to go into is vascular spasm. Well, how do you classify vascular spasm? Whenever there's damage to the blood vessel lining. So look here, let's say that we damage these endothelial cells right here. They're damaged.
So look at them. They're damaged. And maybe we damage some underlying tissue also. So these guys are damaged now. Whenever these tissues are damaged, what can happen?
Blood can leak out, right? Well, we don't want the blood to leak out into this area because then if we start losing blood volume, that can lead to a lot of problems, right? So we don't want to lose a lot of that blood.
So what we want to do is we want to be able to prevent this blood loss from occurring. So we want to contract or constrict the blood vessels. And by constricting the blood vessels, we decrease the amount of blood that's being lost.
That's what we want to do. That's vascular spasm. What causes these smooth muscles here to contract?
Let's go into that. First thing, whenever these smooth muscles are injured, I mean whenever these endothelial cells are injured, they secrete a chemical and this chemical is called, I'm going to put it with an E, endothelin. So what is this chemical called?
It's called endo... And what does endothelin do? You see this purple receptor down here in the smooth muscle?
Look what he does. He comes over here and he binds on to that purple receptor. And he activates an intracellular mechanism. And that intracellular PIP2 calcium signaling mechanism will cause contraction. And whenever that smooth muscle contracts, so again, what's happening here?
There's going to be contraction. That's the overall effect. And what is contraction going to do? It's going to cause vasoconstriction, which is going to decrease the diameter of the blood vessel and try to prevent the blood loss.
That's one mechanism. Second mechanism, again, what's the first mechanism here for vascular spasm? So we have vascular spasm.
This is our first event. The first event is endothelin. While we're at the muscles, let's do one more mechanism.
So endothelial effect, right? The second thing is, there's what's called a myogenic mechanism. So whenever you have direct contact or injury to the blood vessel wall, and it actually causes direct injury to the smooth muscle, Whenever there's direct injury or contact with the smooth muscle, there's a protective mechanism in response to that and it's called a myogenic mechanism. So if there's direct injury or contact, the smooth muscle will contract. So again, what's the second mechanism?
This is called a myogenic mechanism. Okay, so it's whenever there's direct injury or contact with the smooth muscle, it contracts. Third event. You see these orange receptors here, these orange neurons? Whenever there's inflammation, you release specific types of inflammatory chemicals.
So there's a lot of inflammatory chemicals within this area. A lot of inflammatory chemicals like maybe some histamines and some leukotrienes and some prostaglandins. What are they gonna do? They're gonna stimulate these actual orange neurons, right? These nociceptors.
And whenever they're stimulated they're gonna initiate pain but that pain reflex can cause vasoconstriction. So whenever these neurons are stimulated, these nociceptors, due to local inflammatory chemicals or mechanical trauma, so in other words, there's direct injury to them as well, they're gonna initiate a reflex that causes contraction. So again, what will happen here?
He can initiate contraction onto this actual smooth muscle cell. And whenever there's contraction, that will cause the vascular spasm also. So again, what's the third effect?
Noiceoceptor activation. So three mechanisms. that triggered this vascular spasm event, right?
So that's that part. Now, let's go into the second event, because we've already gone over how we're trying to prevent this from happening. Let's go over here and do the second event. What's the second event now? All right, so now, when there's damage to these endothelial cells, right?
Damage to the endothelial cells may be damage to the collagen, may be damage to the smooth muscle. What happens is there's a protein. There's a protein produced by the endothelial cells. Look at this. See this protein right here?
This protein is called VON. Vonn-Wildebrand factor. Vonn-Wildebrand factor.
So again, what is this protein called? It's called Vonn-Wildebrand factor. So this protein, it's secreted by the injured endothelial cells, right? And what happens is, normally the platelets love to bind to the collagen because it is Vonn-Wildebrand factor.
If these cells are injured, can they release nitric oxide? Can they release prostacyclin? No.
So the platelet is not kept inactivated. So that platelet is actually going to bind. And on top of that, if we don't have heparin sulfate, because maybe it's damaged and there's heparin sulfate right here, can we keep some of those clotting factors inactive?
No. And if we have thrombomodulin right there and that was damaged can we actually keep the blood thin from factor V and factor VIII? No. So this would trigger that coagulation cascade right? But first we need to do platelet plug.
So again nitric oxide and prostacyclin is inhibited and then the platelets will come and bind here. So look here's a platelet right here and here's a platelet right there. They'll bind.
But on the von Wildebrand's factor, so let's say here's the von Wildebrand's factor, there's a specific receptor on the platelet that binds with the von Wildebrand's factor. What is this glycoprotein called? And the only reason I mention it is because it's important because we have to understand certain diseases and drugs.
That protein right there is called, that black protein is called glycoprotein 1B. So again, what is that protein called right there? It's called glycoprotein 1B and it binds with the von wildebrandt's factor. So the platelets bind here, right?
And then what happens? Well, once the platelets are actually going to be like activated because of this binding, their granules start actually releasing specific chemicals. What are those chemicals that it secretes?
Three chemicals it secretes. One of these chemicals is called ADP, right? That's one really, really important one.
Another chemical is called thromboxane A2. And another chemical that secretes is called serotonin or 5-hydroxy tryptamine. What do these chemicals do? Well, I told you before that there's platelets just kind of naturally circulating within this area right here, right?
So maybe here's a platelet, maybe here's a platelet, maybe here's a platelet, here's a platelet, right? These platelets are just tiny little cytoplasmic fragments. They're super, super tiny. They're derived from a megakaryocyte, right?
So what happens is ADP and thromboxane A2, these guys work to be able to stimulate these actual platelets. So they have receptors on their membrane. that specifically bind the ADP and the thromboxane A2. So when ADP and thromboxane A2 bind onto these platelets, it activates the platelets and causes these platelets to want to come to that site of injury. So then what's going to happen?
These platelets are going to start aggregating to that site of injury. So they're going to undergo, what's this called whenever they come here? It's called platelet aggregation. That's the first step.
All right? So now the platelets are going to start binding here. So look at what's happening here. So platelets bind here.
They bind here. They bind here. And they start forming this nice plug right here. But then there's one more thing that we have to do before we keep going on with this, right? So the platelets are binding.
But how are they binding to each other? We know how they bind with von Wildebrand's factor. Let me draw a platelet right here. So here's one platelet. And here's another platelet.
So we know that they can join with the von wildebron factor right? So here's the let's say here's a von wildebron factor protein. They bind with that with the glycoprotein 1B right?
So here's our glycoprotein 1B. That's how they bind this. But how do they bind to each other? Well, here's another. There's these proteins here on each one's surface.
And then there's a thing called fibrinogen, which actually links them together. This protein right there is called, get ready, glycoprotein 2B3A. Holy goodness, right? So that's a crazy name right there, but it's important because we have to know these proteins because they're drug targets. Okay, so again, glycoprotein 2B and 3A with fibrinogen between them link the platelets.
together. So that's what you'll see linking them together. But now look we got a nice platelet plug. Okay we're not done yet. What is thromboxane a2 and what else does serotonin do?
We see these actual pink these purple receptors down here. Thromboxane a2 and serotonin love to bind to the smooth muscle and when they bind on to the smooth muscle they cause contraction. So again what would they cause? Let's come down here they cause contraction, right?
And what does contraction cause? Contraction leads to vasoconstriction and then again what will that vasoconstriction do? Enhance the vascular spasm effect.
So again ADP and thromboxane A2 cause platelet aggregation which leads to this platelet plug. But thromboxane A2 and serotonin cause vasoconstriction to enhance the vascular spasm response. That is the second step. So what is the second step right here that we've done? It's called platelet plug formation.
Not bad, right? All right. So again, we've done the second step. So we've done first step, second step.
Now let's go on to the third step. Okay, so now real quick recap this will be, right? So again, there's damage to this endothelial lining.
We already know what happens. Von Olderbron's factor is going to be right here, right? And it's going to have its specific proteins there.
What's going to bind? Platelets, and they're going to bind with their glycoprotein 1B. They're going to bind to each other through their glycoprotein 2B3.
with the fibrinogen in between them. They're going to start becoming activated and secreting ADP and thromboxane A2 which causes platelet aggregation and then they're going to secrete serotonin and then thromboxane A2 also will cause vasoconstriction to enhance vascular spasm. So now we got this beautiful platelet plug here.
Now we go into the bear of it all, all right? Now we're going to go into coagulation. Okay, so now we're talking about the coagulation cascade. So first off, these platelets, so they've already undergone aggregation and the plug formation, and they just continue to keep pulling more platelets to that site. But once this has happened, we go into this next step, right?
So there's these things called phosphatidylserine groups that are going to be on present. present on the platelets membrane and it creates these negative charges right here. So these negative charges on the actual platelets cell membrane and this is again caused by phosphatidylserine. There's going to be proteins, you know your liver, here's your liver right here. So your liver is constantly making tons of clotting proteins, tons of clotting proteins and these clotting proteins are normally circulating within the blood plasma, right?
But they're kept inactive. But now we're going to activate them. that just so happens to be walking through this area and then boom interacts with the platelet is called factor 12. So what is the first protein called?
It's called factor 12. or Hageman's factor, right? So there is factor 12. Factor 12 will interact with those negative charges on the platelet and then convert itself into an active form. So it's a precursor, or a proenzyme we can call it. A proenzyme, right?
Or even we can call them zymogens, they're just inactivated, right? Well we're going to activate them now. So now here's factor 12, he's activated.
What happens next is, factor 12 activates factor 11. So here we have factor 11. Factor 11 is going to get activated by factor 12, so now he's activated. And then factor 11 is going to go and activate factor 9. So here's another one. So here's going to be factor 9. So factor 9 right here is going to interact with factor 11, and he'll be activated.
And then what happens? Factor IX interacts with another protein that just happens to be walking by, and that is going to be called Factor VIII. So over here is actually going to be factor 8, and factor 8 is going to interact with factor 9, and they're going to form a complex, right?
but they're going to need two other things present for this to happen. They're going to need what's called platelet factor 3 and calcium. So they need calcium as a cofactor, and then they need the membrane of the platelets, or platelet factor 3, in order for this complex to occur.
Then there's another protein here, and this protein is called factor 10. And factor 10, so these guys are actually going to combine together, and they'll form 1. complexing pathway right here that will drive the conversion of the inactive form of 10 into active form of 10 and now the active form of 10 is going to react with another protein I know this is a lot of proteins here but it's going to react with factor 5 so factor 5 will actually react here you'll also have platelet factor 3 and calcium driving this step also. And what this will do is this will activate another protein, and this protein is called the prothrombin activator. So this is called the prothrombin activator.
Okay, now what the prothrombin activator does is it has, look at these ears. Look at these ears. What it does is, there's another molecule kind of circulating within that area and that molecule is called factor two.
But in this form it's called prothrombin. It's in the inactive form. So what the prothrombin does is, look it reacts with the ear of prothrombin activator, reacts with him. And when it does, it converts the prothrombin into thrombin, the activated form. So factor two is also called thrombin.
Okay, know that. Factor two is also called thrombin. Thrombin then does what? Okay, here's where we get to the good stuff.
Thrombin reacts in two ways. One, there's a molecule which is called, look, I'm going to draw it in like a circle here. They're kind of just hanging out in this area, these little circles.
What are these little circles called? These little circles are called fibrinogen. So this is called phi.
Fibrinogen. And fibrinogen is a plasma protein, if you remember from the hematocrit, that is actually accounting for some of the 4% of the plasma proteins, right? And it's circulating through the blood soluble-wise.
It's soluble within the blood plasma. But then what happens is factor 2, or thrombin, polymerizes them, starts linking them together. And if he starts linking them together, look at what they're gonna look like now. So now, how many do I have? 1, 2, 3, 4, 5, 6, 7. So I have to have seven of these together over here.
So three. Four, five, six, seven. What is this molecule here called? This is called fibrin.
And fibrin is insoluble in the blood plasma. So this is going to help to turn the blood from more of a liquid into a jelly-like substance. That's the purpose of coagulation. Because we want it to be more jelly-like so that it will slow down the blood flow beyond that area. Because we don't want to keep losing our red blood cells.
So it slows that flow of the red blood cells through there and turns it into more of a jelly-like substance. All right, so now it's insoluble. One more thing.
It reacts with another protein over here. And this protein is called factor 13, also called the fibrin stabilizing factor. And look what he does. He becomes activated. And you need calcium also for this step to occur.
So what else do you need for this step to occur? You need calcium. Factor 13 will then take these fibrin strands and cross-link them together. So then it'll take another fibrin strand that it might have over here somewhere, that thrombin's polymerized, and look what it's going to do. It's going to cross-link them.
So it's going to take this one, cross-link it this way, and then it might cross-link another one over here. What's the purpose of cross-linking this? The purpose of cross-linking it is to create a nice fibrin mesh so that when we lay this over the platelets, it prevents the platelet thrombus from dislodging and going into an area and causing an embolism right we want to keep this taut nice and held down so that we don't have any blood loss from here but we also don't let it break off that's important so again fibrin stabilizing factor will cause this cross-linking so again what will it cause here it'll lead to cross-linking of fibrin and this produces the Fibrin mesh.
So what is this molecule now called? It's a fibrin mesh network, right? Now, what does this fibrin mesh do?
This fibrin mesh is going to be laid over this. So now imagine here, I'm just going to draw it as lines now. Look, look at this.
We're holding this down now. And here's our cross-linking. There's our fiber and mesh and that's holding that platelet plug in place so that it doesn't dislodge and go somewhere else, right?
And also it's keeping the blood as it's circulating through this area right here more jelly-like, more thick, more viscous. That slows the blood flow down so we don't continuously have blood loss, right? All right, so what have we gone over then? So basically, let me tell you real quick here. We have two pathways.
An intrinsic pathway. In an extrinsic pathway, I haven't talked about the extrinsic yet, but I will. It's a very quick pathway. But intrinsic is the ones that we just talked about, where we started with 12, right? And we went from 12 down to 11, and then 11 down to 9, and then 9 with 8, and then 8 combined with 9 to activate another one, which is that factor 10, right?
And here, let me tell you one more thing. Factor 10 getting activated, this is the common pathway. So now, what we just went over here is the intrinsic pathway, right? And the intrinsic pathway is the pathway that's occurring inside of the blood independent of the extrinsic pathway. What do I mean?
If you take someone's blood out of their, you take someone's blood and you put it in a tube that's not heparinized, so it doesn't have heparin coating it, right? The glass has a roughened surface, a charged surface. So what does that do?
It activates factor XII. So the intrinsic pathway can occur... inside of a test tube independent of the extrinsic pathway. However, the extrinsic pathway, which we're going to talk about, does depend on some of the factors and proteins within the intrinsic pathway.
Alright, before we do that, again, know that what we covered intrinsic is 12, 11, 9, 8, and then activating the common pathway, which is 10. That's going to be super important because now, you see how there was tissue damage here? Whenever there's damage to any of our tissues, Our tissues release a protein which is called tissue factor or factor three. Factor three.
Now factor three will come over here and look what it will react with. It will react with another protein over here and this protein is called factor 7. So this protein is called factor 7. When factor 7 reacts with this factor 3, it becomes active. And look what it can do now. It can do two things.
One thing is it can stimulate this step. You see how it can actually push factor 9 into becoming activated? Well look what else it can do.
It can also converge. right here onto the common pathway. It can converge right onto the common pathway, right?
So now, what do we know out of this then? So what do we know is we know that factor three can be secreted by damaged tissue cells and those tissue cells will then actually activate, they'll produce tissue factor, factor three. Factor three will act with react with factor seven and then factor seven can activate factor nine and it can come into this Common pathway. That is the extrinsic pathway. So what is this pathway here again?
Let's write it up over here. So again, what is this pathway called? This is the extrinsic pathway. And again, how does this pathway occur?
What is the protein produced by the damaged tissue cells? This is factor 3. Factor 3 will react with factor 7. Factor 7 will be activated and factor 7 can drive the activation of factor. 9, as well as he can also drive the activation of the common pathway. So what is the big thing about this?
Look how much longer it takes for the intrinsic pathway to occur versus the extrinsic pathway. The extrinsic pathway can occur in about 30 seconds. It's very fast. Whereas the intrinsic pathway might take about 4 to 6 minutes to occur.
So it's a little longer, right? So now, now that we understand that, we understand the activity of the intrinsic and extrinsic pathway. How the extrinsic tries to drive either factor 9 activation or it can act try to activate factor 10. And then the intrinsic pathways the sequence of cascade that also desires to activate factor 10, which is again the common pathway. Alright, so I know coagulation is a pretty big beast. It takes a lot to remember all these proteins.
So I wanted to give you a little trick to help you to remember it. Alright, so here's the thing. On the left we're gonna have the intrinsic pathway here on the right we're gonna have the extrinsic pathway It's just a little trick you can take it if you want to so what I do is X-marks the spot so I put that it's the first thing I do put it right in the middle then after that I count downwards starting with 12 Skipping 10 so in other words I put X X marks a spot That's 10 and I work backwards from 12 12 11 skip 10 9 8 and then I go to 10, right? So look here 12 to 11 11 to 9 9 to 8 and then 8 to 10. Guess what pathway this is?
This is the intrinsic pathway, right? So this is the intrinsic pathway. Again, what do I do? X marks the spot, so 10, and then again I count backwards from 12 just skipping 10. 12, 11, skip 10, 9, 8, and then I get to 10. How do I remember the extrinsic pathway?
Extrinsic, you can remember 3 plus 7 equals 10. That's easy right? So again count backwards from 12 and then 3 plus 7 equals 10. Now how to remember the comet pathway and then the formation of thrombin in the fibrin mesh. So in order to make 10 right because it's gonna this is gonna go downwards but in order for me to remember this I remember 5 times 2 times 1 equals 10. So what is we have factor 5 right that active reacts with 10 and then 10 and 5 activate 2, which is thrombin, right? So 2 is thrombin. And then 2 activates 1. What is 1?
Fibrinogen. So again, how do I do it? X marks the spot, 10. Count backwards, starting with 12, skipping 10. So 12, 11, 9, 8, and then you hit 10. How do you remember the extrinsic? 3 plus 7 equals 10. And then how do you remember the formation of the thrombin? So you have, remember, 5 times 2 times 1 equals 10, right?
So 5 is going to be who? Factor 5. 2 is going to be thrombin, and then thrombin is going to be activating fibrin. So you can remember that.
Again, 10 with 5 activates 2. 2 activates 1. So that's a very quick, easy little trick to be able to remember the coagulation cascade. Okay. So again, what have we done?
We finished this third step which is coagulation cascade. So we finished the third step, coagulation cascade. Now let's go into the fourth step. So again, what do we have over here? We had damage to the endothelial lining, right?
It's just a constant review of this guys. So again, damage here. Then what do we have on wildebron's factor here? Then we have our platelets here. Here's our platelet plug.
The platelet plug is releasing tons of different chemicals, right, causing the platelet aggregation, causing the platelet plug formation, vascular spasm. Then we have the coagulation cascade, which is leading to the production of the fibrin mesh with the intrinsic and the extrinsic pathway. Now we go into our fourth step. What is the fourth step?
The fourth step is called clot retraction. and repair. So you see these platelets they have contractile proteins within them it's called actin and myosin so what they do is imagine imagine my arms are the platelets right so imagine I'm the platelet right here what I'm gonna do is I'm gonna take one arm over here and I'm gonna grab I'm gonna grab the endothelial cell on this side and I'm gonna grab the endothelial cell on this side what I'm gonna do is I'm gonna pull the edges of the endothelial cells closer together.
By doing that I'm bringing those ruptured edges of the blood vessel closer together. So again what does the platelet do within this step? The first thing that's going to happen is platelet contraction and that will pull the ruptured edges of the blood vessel closer together.
Second thing that's going to happen It's going to secrete a chemical, these platelets nearby are going to secrete a chemical which is called platelet derived growth factor. So this chemical is called platelet derived growth factor. What does this platelet-derived growth factor do?
The platelet-derived growth factor comes down here, and if these smooth muscle cells were damaged, so let's say that these smooth muscle cells were damaged right here, there was damage to these smooth muscle cells, the platelet-derived growth factor is going to trigger the mitosis, or proliferation of the smooth muscle lining. And on top of that, if there was any damage to these connective tissues here, it's going to cause connective tissue pacts. patches to be formed to regenerate those collagen fibers. So it's going to help to produce connective tissue patches to repair the collagen, maybe even produce connective tissue patches over this endothelial cell area, and it's going to help to proliferate the smooth muscle to renew that lining.
So again, what is this chemical here called? This is called platelet derived growth factor. What is the third thing that happens?
There's one more chemical and that chemical is called vascular endothelial growth factor. And again, the playlist will secrete that chemical. So again, what is this chemical called? This is called vascular endothelial growth factor.
What do you think it does? It says it within its name. The vascular endothelial growth factor is going to regenerate the new endothelial lining. So any of the endothelial lining that we damage, it's going to help to regenerate that.
Okay, so again, clot retraction repair, it's going to contract, pull the ruptured edges closer to one another, secrete PDGF to proliferate the smooth muscle. and produce connective tissue patches here, and then it's going to release vascular endothelial growth factor, which is going to replenish the new endothelial lining, and it can lead to what's called canalization, but we're not going to do that here. That's the fourth step. Alright, so this last step here, this last step, the fifth and final step for this process is called fibrinolysis.
So, you remember here that we had that clot, right? Now, This area can get pretty big and sometimes it can get so big that it can actually occlude the blood vessel flow beyond that area and lead to ischemia right so we don't want that. So what we want to do is is we want to be able to get rid of that clot we want to bust that clot up. So there's natural proteins present here on the cell membrane here. So what is this protein called right here?
This protein right here is called they have two names for me call them tissue plasminogen activator sometimes they even call it streptokinase but We're going to just call it tissue plasminogen activator. So what does a tissue plasminogen activator do? There's a protein naturally present within your bloodstream again.
And this protein is called plasminogen. It's called plasminogen. And plasminogen will react with the tissue plasminogen activator and get converted into what's called plasmin. And imagine plasmin.
as though he's like a hungry little eater here. So look, he's got nice little teeth in here, right? And he's ready to eat.
What he's going to do is he loves to eat fibrin, okay? So he loves to eat fibrin. All right, I love fibrin, right? So what he does is he's going to come over here and he's going to start digesting that fibrin mesh.
He's going to start cutting that fibrin mesh up. And what is he going to do then? By degrading the fibrin mesh, He might release a little bit of fibrinogen out here, which remember was the precursor.
And he also might release a very, very important chemical called a D-peptide or a D-dimer. Why is this important? When they run specific blood tests to determine if someone's had some type of clot formation, they run a D-dimer.
It's really important because we run a D-dimer and we see elevated D-dimer levels. That can help us to understand maybe this person has had some type of clot formation. So D-dimer is very important for diagnostic procedures within differential diagnoses, right?
So again, what is this going to do? Plasminogen to plasmin? It's going to digest the fibrin and bust that clot up, right? And by busting up that clot that helps to be able to prevent occlusion to the blood vessels, right? One more thing, why is this TPA important?
We give this to people who have some type of a stroke, so if they have some type of trans-endoschemic attack that's blocking the occluding the blood flow to the cerebral vessels, The TPA, we're going to give that to them in the acute response within hours. You need to give it within hours because they also give aspirin in response to this too. But TPA, what is it going to do when you give it to them?
It's going to make plasmin. What's plasmin going to do? It's going to start breaking down that fiber and mesh to get rid of that blood clot, right? And that's important because we don't want to have too much blood loss to a specific area within the brain because it can lead to excitotoxicity and that's what leads to the damage to some of the neurons within that area. And it can lead to limb weakness and problems with that, right?
Alright, so that covers our fifth step which is fibrinolysis. Let's come back over here, do a quick recap of everything, and talk just really, really briefly about a couple drugs. Alright, so again, what was that first thing that we wanted to go over again?
What keeps the blood naturally thin? The nitric oxide, the prostacyclin, and activates the platelets. The heparin sulfate, the antithrombin 3, and activates some of these coagulating proteins, procoagulant proteins, and then thrombomodulin, thrombin, and protein C, and activate other procoagulants.
So again, this is all our step one, but it's again, It's what keeps the blood naturally thin. What kind of drug could we use here to enhance this process if someone needs to be able to prevent themselves from having a clot? Well, you know antithrombin 3?
We can give a molecule called heparin. And what does heparin do? If we give more heparin, it's going to enhance antithrombin 3 activity. If you enhance antithrombin 3 activity, what are you going to do?
You're going to destroy a lot of these procoagulants, keeping the blood naturally thin. Alright, what's this first step here that we went over? Vascular spasm.
What's the whole purpose of it? Just to be able to keep blood from prevent blood from continuously being lost right? By how? Vasoconstricting the blood vessel and preventing as little blood as possible from leaking out into the tissue spaces right?
And causing hematomas and other damage. Severe blood loss right? That's important there. Second step, platelet plug formation.
Again what was the whole purpose here? The platelets love to bind with the von wildebrand factor. Okay now one more thing here. When these platelets aggregate right?
how can we prevent the aggregation? Well, you remember ADP? ADP, there is a drug that can actually block ADP. This drug is called clopidogrel.
So what does it do? It inhibits ADP. That's one drug that you can give.
Another drug that you can give inhibits the formation of thromboxane A2, which is a COX-2 inhibitor. And this is called, everybody usually knows this one, this is called... Aspirin. And aspirin inhibits thromboxane A2.
You can also give a drug to block this glycoprotein 2B3A protein, right? And this is called ab6amab. And ab6amab inhibits the activation of the glycoprotein 2B3A connection.
So a lot of things that you can do. You can also give direct proteins in here. You can actually give some specific inhibitors.
You can actually give direct thrombin inhibitors. You can give, I'm sorry, direct factor 10 inhibitors and you can give factor 2 inhibitors. Common factor 2 inhibitors are like dabigatran or pradaxa.
As the brand pradaxa or dabigatran atexylate, that can inhibit this enzyme right there. Okay, so there's a lot of different drugs that you can give here to be able to treat some of these conditions, right? You can also give warfarin. And what is the purpose of warfarin?
Warfarin is a vitamin K oxide reductase inhibitor. What the heck does that even mean? You know there's specific proteins like factor 2, factor 7, factor 9, factor 10, protein C, protein S, a whole bunch of different proteins, they require vitamin K.
What warfarin does is it inhibits the enzyme that actually pushes that vitamin K into these enzymes making them functional. So if you don't have vitamin K what's going to happen to these procoagulants? They're going to be inhibited and not functional. That's another drug that you can give someone to be able to inhibit the clot formation. So again, that's in a nutshell everything we're going to need to know about hemostasis and just a very basic amount of drug information that we can go to understand a little bit more about that path.