Hi, Andrew Wolf here. In this video, I'm going to be talking about the physiology of hemostasis. Now, I want to start out by sort of talking about two different mechanisms of injury which both lead to different pathways in the formation of a clot. So, uh first of all, we're going to talk about uh vessels that are just um occurring on inside the vessel. So, these are intrinsic to the vessel and you may have heard of the term intrinsic pathway. Now, I'm going to talk about the intrinsic pathway here, but I'm also going to talk about something that is separate from the intrinsic pathway um called platelet plug formation. But these are both things that are happening inside an intact vessel. Okay. Now, on the other side, there are things that cause damage to tissues or disruption of the vessel. And this is going to stimulate the exttrinsic pathway. So intrinsic when I talk about things inside the vessel, I'm going to talk about platelet plug formation. And then I'm going to talk about the intrinsic pathway. And when I talk about exttrinsic, um I'm talking about things that um that disrupt the vessel wall. Now you know this is interestingly enough um you know vessels are very especially when you get down to the capillary level or the um you know arterial or venial level um it doesn't take much of an injury to disrupt the vessel wall. So in reality these two systems are almost always working concurrently. So we separate them in a way to understand them. But um just remember that in real life it's rare for an intrinsic for the intrinsic um mechanisms to be initiated without the exttrinsic mechanisms being being initiated and vice versa. Okay. So we're going to start out with injuries to the vessel wall. So we're going to take a small vessel here and like a normal vessel it is lined by the endothelium. So we have endothelial cells and a basement membrane. And remember this is the uh lining of all blood vessels in the body have endothelial cells and the heart itself have have essentially the same cells. Now endothelial cells, the endothelial lining is the only surface known in the world that um that blood can flow through without clotting. Now you know we have been working for many many years to create surfaces that um that will not initiate clotting but we haven't been able to do it yet. There is no system um there is no surface like endothelial cells. Endothelial cells are covered with sort of anti-coagulant proteins that prevent the coagul coagulation system from being initiated. And we know what some of these are and I'm not going to get into it. We know some what some of them are and there are others that we don't understand yet. Now, inside the blood vessel, we've got little platelets. And if you remember there, our picture in the prior video on platelets, they're these little uh fragments of cells with sort of little spinus processes that stick out of them. Now, what activates platelets? Well, one of the main things that activates platelets is if we have a endothelial cell that is damaged and disrupted, this endothelial cell will secrete chemicals will secrete a protein called vonilibbrand factor and von willilibbrand factor u activates platelets and makes them sticky. So this von willilibbrand factor will be excreted by this injured cell and activate the platelets. So we have von willilibbrand factor activates platelets and the platelets form form a plug and the exact mechanism by which this occurs is um proteins on the surface of platelets um start are actively binding with fibbrronogen and we get linkages between platelets. Now fibbrronogen is an important uh protein to know about. It is actually a inactive clotting protein in the in the body and it will be activated later on um to become fibbrin. But in this instance when it is binding platelets together and being part of the platelet plug it is still in in what what is known as the fibbrronogen or inactive form. So the only reason it's working here is because there are proteins here on the platelet surface that are now being expressed because of von willilibbrand factor that cause the fibbrronogen to bind with the platelets and create cross linkages and that's how we end up with a platelet plug and this is all in occurring due to damage from endothelial cells inside the blood vessel. So again this is just this is platelet plug formation. Okay. Now the next thing that is that can happen inside a blood vessel is uh initiation of the intrinsic pathway. Now this occurs I'm going to draw a little blood vessel again and you know typically with a nice healthy blood vessel our endothelial cells are make an impenetrable barrier. But what happens is if we have significant injury then the blood is exposed to this basement membrane below the endothelial cells. And in the basement membrane particularly when it gets injured enough we get these free ends of collagen proteins sticking into the in to the lumen of the blood vessel. Now, collagen binds with protein in the bloodstream and causes them to um change confirmation. And what it does that the protein that it's binding with is called coagulation factor 12, otherwise known as haggamin factor. and Hagaman factor becomes activated. It changes from factor 12 to factor 12 A and that just means that it has changed shape. So now it has an active binding site and factor 12 A binds with factor 11 and causes 11 to change to its active form 11 A. And then um this cycle continues where 11 A activates 9 to turn into its active form of 9 A and then 9 A causes 10 to turn into its active form 10 A and then 10 A causes prothroin. to turn into thromben. And thrombin causes fibbrronogen to turn into fibbrin. And then fibbrin um fibbrin creates long chains called a polymer. And then these long chains are sort of linked together in in a fairly random fashion by a factor called 13A. Here I'll draw that in a different and it creates cross linkages between the two. So the bi fi fibbrin creates this mesh this really complex sort of basket weave pattern and that is what is the end of our clot clotting system. Okay. So now you don't need to know all the names of this but I do want to make a couple points here. Um number one is why do we have so many steps here? We've got you know step one where a collagen is binding uh with haggman factor stimulating the hagaman factor and then haggamman factor is stimulating another factor and another factor and another factor and another factor. Now actually a lot of these active proteins are actually proteasis and what they do is they take a really complicated protein and they cleave it and break it up. And when it it is cleaved, it end you end up with a active form with with receptors on it that is now active. When it was put together, those receptors were um just sort of bound within this huge matrix of a complex protein. But when it was cleaved by a proteiase, it was broken up so that one piece of it had has active components to it. So a lot of these factors are actually proteuses that are actually breaking up inert inactive complex proteins into active parts. Okay? And um if you can imagine the reason why we have so many steps is because it's a system of amplification. Now I used to use the example of a phone tree but I think the technology is such that people aren't going to understand that as well. So I think the analogy that works well is a viral video where you have you know you've got Hagaman factor that that um you know maybe creates a little video of some damage to a blood vessel and it looks very fascinating. So Haggamman factor goes out and tells three friends and then that those three friends tell three more friends and those three friends tell three more friends and as you continue uh your multiplier gets bigger and bigger and bigger. So this is a system of the reason why there are so many steps and the body has de devised the system with so many steps is because each system amplifies the prior step by a significant factor. Now, interestingly enough, the intrinsic pathway that starts with um collagen activating haggamin factor is um very important to understand because it's involved um significantly in in um the pathophysiology of thrombboism. Um however it's interesting to note that um although this was actually the system that was first understood but now we are realizing that it is the the less important of the two major coagulation pathways and we know that because if someone has a significant has a complete absence or a um significant significant deficit of haggamin factor they u very rarely have bleeding diiathesis and they are able to survive um a long and healthy life without haggamman factor and that sort of underscores the fact that it is the exttrinsic pathway that is the more important pathway in um in providing hemostasis. Okay. So let's talk about the exttrinsic pathway. Okay. So ex the extrinsic pathway all starts out with a a protein called tissue factor and it's also known as factor 3. Now this factor is a protein that um that actually can be in three different that is found in three different places in the body. There is this is just a tissue cell and the tissue factor is found inside the cells. It's found on some cell membranes and and it's also found in extracellular fluid. So there's sort of three different places where tissue factor is found. Now, so the tissue factor again like all the other co coagulation proteins is exists in an inactive form. So what can activate it? Well, there's several different things. Inflammatory cytoines. This is important to realize because you actually can have inflammation without um without tissue injury and this can cause um initiation of the coagulation cascade. Um this is an important component to realize in sepsis and it's what also what um allows our body to uh create abscesses to sort of wall off infections because you end up with you know if you have if you have a group of cells that are infected with bacteria um the fibbrin will actually cause the area to be walled off over time and you'll end up with an abscess and the abscess is surrounded by a very strong um wall that is made up of fibbrin. Okay, so cytoines themselves can activate tissue factor and cause it to turn from its inactive form to its active form. Okay. The second thing that can activate tissue factor is cell injury. And the third thing is vessel injury or vessel disruption. And one of the major pathways that that um activates um tissue factor here is just blood in the tissue. And I'm not sure exactly which protein in the blood is involved in this. There's probably several. But blood in the tissue will activate um tissue factor as well. Okay. So let's talk about what happens. So any of these three things causes um will cause tissue factor to turn into its active form. Now the active form um factor 3A will cause factor 7 to turn into its active form 7 A and then 7 A will cause factor 10 to turn into 10 a. Now you'll recognize this step here because 10 going to 10 a also happens in the intrinsic pathway as well. So the rest of this pathway 10 to 10A prothroin to thromen and fibbrronogen to fibbrin is called the common pathway because this common pathway um occurs in whether it's part of the intrinsic or the exttrinsic pathway. Okay. So we're going to focus for now on the common pathway and just just keep in mind that once you get down to 10 um being transformed to 10A the rest is is in common and it's actually fairly simple 10 to 10 A prothroin to thrombin fibbrinogen to fibbrin. Okay so we're just going to kind of go through that again. Okay, so we've got 10A uh 10A activates proth thrombin and proth thrombin becomes thromben. Now thromben is a protease and what thrombin does the way that it activates fibbrronogen is so fibbrronogen is this long strand that has sort of a little globulin at the end and then another long and then another fibbrronogen long strand with a globulin at the end. And what thromen does is it cleaves this fibbrin. That means it breaks it into two. And what is exposed here is a receptor where fibbrin can bind to itself. So you end up with you end up with this connection here where the fibbrin binds to itself and then you end up with these very long strands of fibbrin. And if we sort of so you end up with these long strands called fibbrin polymers and you know they're as strong as collagen strands. So they're very strong in straight proteins and this doesn't finish the situation. So this is fibbrin polymer polymerization. But then we end up with lots and lots of fibbrin polymers. And the final act in clot formation is activated factor 13 or 13A. um binds these together to create these this thick weave of fibbrin fibers. Okay, so that brings me to an end of this uh this brief video on the physiology of uh hemostasis and the coagulation cascade. Please let me know if you have any questions and take a moment to um to provide feedback and a thumbs up or a thumbs down. Um, and in our next video, I'm going to talk about the uh very important factors that control uh the coagulation cascade. I'll see you there.