Coagulation cascade | Human anatomy and physiology | Health & Medicine | Khan Academy
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Coagulation cascade | Human anatomy and physiology | Health & Medicine | Khan Academy

– Let’s say this is a blood vessel and it’s made up of
these endothelial cells, the same way that all blood vessels are. Let’s say that this blood
vessel gets into a fight and it gets a little bit hurt. So, the walls break open
and the cells now no longer seal the vessel from what’s around it. When this happens, we
wouldn’t want all the blood in this vessel to come
pouring out of the vessel because we’d lose way too much blood. So the body has a method
of containing the blood. The first thing that’s
going to happen is that little platelets, which are
circulating in the body, are going to come and deposit there and form an initial plug. So these little things are platelets. But it turns out that this
plug is not quite solid enough, and so the body needs a second mechanism to solidify the plug. And that mechanism is what we’re going to talk about most in this video. I’m drawing that mechanism here. What I’m drawing is little fibrin strands, which will come and act as a kind of mesh to hold the platelet
plug together solidly. So what do these fibrin strands look like? Well, they’re made up of
little fibrin sub-units. These are actually what we refer to as the fibrin molecules or proteins. These, it turns out,
have a natural affinity for each other, so that when
you bring them together, they form a polymer. They join end to end and
they create a fibrin strand. So the question then
becomes, how do you make sure that these fibrin units only join together and make a strand at the site of injury? So for example, if you
had a bunch of little fibrin molecules over here, how would you keep them
from joining together? The answer is that you can’t, which is why you don’t have fibrin circulating in your blood. You actually have something else, which I’m going to draw here. That something else is fibrin,
but plus an extra piece. That extra piece, as you can see, covers one of the active
sites of the fibrin and therefore prevents it
from joining to itself. So the name of this thing is fibrinogen, probably because it will form fibrin, hence the fibrinogen. It’s only when you convert
fibrinogen to actual fibrin that the units can join
together and form a strand. So again, to repeat, you don’t have fibrin circulating in your blood,
you actually have fibrinogen. So the question then becomes, how does your body know
to convert fibrinogen into fibrin at the site of injury? The answer is that when you
injure your endothelium here, you’re going to expose
your blood to new proteins. And maybe your actual
endothelial cells will release some proteins because they’re damaged. So basically, you have new proteins that weren’t seen before
and that are seen now. Those proteins will eventually cause fibrinogen to turn into fibrin. So while evolution was designing us, it could’ve said, let’s use
these little yellow guys to convert fibrinogen to fibrin. That might’ve worked, but it’s actually not the most efficient way to do things. The reason is, imagine if
you and a couple of friends have a huge amount of work to do. Let’s say you need to convert a million fibrinogen to fibrin. Is the best way to do it, to actually sit down and crank it out? Or would it be more
efficient to have each of you call five friends and invite
those friends to come work. And ask those friends to
each call five friends. And ask those friends to
each call five friends. Well, obviously that
would get the job done much faster assuming
you had those friends. That’s also what your body does. So actually, it doesn’t
use these yellow guys to convert fibrinogen to fibrin. There’s another player which does that, and it’s an important one, so we’ll give it a
little drawing like that, and it is called thrombin. Thrombin, just like
fibrinogen, is activated from an inactive form,
which we call prothrombin. The prothrombin has a
little piece on the end that prevents it from working,
so this is prothrombin. That piece is removed when
you want to get to work. So is prothrombin activated
by the little yellow guys? Well, actually, he’s not
either because the chain of amplification is much longer than that. To draw the actual amplification cascade, you just need to see it and practice. But there is an easier way to draw it than it usually is drawn,
so we’ll do that now. So let’s say you were
counting down from XII. Normally you would start at XII. You’d go to XI. You’d go to X, and then you’d go to IX. But let’s say that you
weren’t very good at counting. You would start with XII. You’d go to XI. Then you’d make a little
mistake – you’d go to IX. Then you’d realize you
forgot X, so you’d go to X. Now it’s good that you remembered X because X is a big deal, and he’s going to help bring us thrombin. Turns out that thrombin
is also known as II. We know very well that
thrombin helps give us fibrin, which is known as I,
and that’s no surprise because fibrin’s the most important guy. He’s the ultimate goal,
and thrombin is the guy that helps us get the ultimate goal, so he should be number II. Now unfortunately, it’s
not quite that easy. X likes V because they’re
both multiples of five, so they work together and IX likes VIII because they’re right next to each other and so they work together. So this is the first part
of our clotting cascade and it turns out that
we call this part here, the intrinsic pathway
and we can talk about what that means later, but for now let’s just give it its name. But what’s perhaps more
important to be clear about is that in this drawing, XII
is not actually becoming XI, and XI is not actually becoming IX. What’s happening is that
XII, when it’s activated, is a catalyst to convert XI from it’s inactive form
into its activated form, which we’ll draw XIa. And then once XI is activated,
it serves as a catalyst to convert IX from its inactivated form into its activated form. So you see that these arrows are actually more about catalyzing. Now I said that this was
an amplification sequence, so I just wanted to share a little data to show that that’s true. It turns out that this
guy, factor I, or fibrin in its inactivated form,
which is fibrinogen, has about 3,000 micro-grams
per milliliter in blood, while this guy has about 100 micro-grams per milliliter in blood. Meanwhile, X has about 10 micro-grams per milliliter in blood and factor IX has about five micro-grams
of milliliter in blood. So you can really see that
as you go down this thing, you’re increasing your
amounts in your blood, which reflects the fact
that you’re also going to increase the number of active forms of these when you have a clot. But anyway, I said that this
was the intrinsic pathway because there is another pathway, which also leads to an activated X, but in this other pathway,
what activates the X is an activated VII,
which is activated by III, also known as tissue factor. I’ll just write TF for tissue factor. In this pathway, which I’ll circle here – and I apologize for
the poor organization – this one is known as the
extrinsic pathway, extrinsic. So what’s the difference
between these two pathways? Well, it turns out that the
extrinsic pathway is the spark. It’s the one that gets activated by the original insult over here, whereas the intrinsic
pathway is kind of like the workhorse that really gets most of the coagulation done. So how does that work? Well, you first get this tissue factor, which is actually one of
these little yellow guys. And that tissue factor activates VII, which activates X, so you get a shot – a spark that shoots down this way and activates a little bit of X. And then X will activate
a little bit of thrombin, and then thrombin will get
the intrisic workhorse going. And how will thrombin do that? Well thrombin actually activates a whole bunch of these guys, and to remember the
ones that it activates, you just need to take the five
odd numbers starting at five. So what is that? That’s V, VII, IX, XI, and XIII. Actually, this is just almost right, but it actually turns
out that it’s not IX, it’s VIII because it
couldn’t be quite that easy. So those are the five that it activates. So let’s draw that in here in our drawing. So let’s draw that in
the form of blue arrows because thrombin is blue. We said it’s going to activate V. We said it’s going to activate VII. We said it’s going to
activate not IX, but VIII, so this will be an awkward arrow to draw. We said it’s going to activate XI, and we said it’s going to activate XIII. Where’s our XIII? Well, we haven’t actually drawn it in yet, so let’s quickly chat about that. The end goal of this whole cascade is to get these fibrin molecules, and these fibrin molecules together will form some strands. It actually turns out that
there’s one more step, which is to connect
these strands together. So we’re going to want
to connect these strands together with some cross links. These cross links will
just hold them together so that they actually form a tight mesh. It turns out that it’s
this step right here, which is enabled by factor XIII. So let’s draw the final thrombin activity, which is to activate XIII. So you can see that once you
activate a little thrombin, it’s going to activate
all the necessary things in this intrinsic pathway to get it going. You might actually be
wondering about XII up there because thrombin is not hitting him, and actually it turns
out that if you remove a person’s factor XII, they
can still clot pretty well. So it’s clear that XII is
not a totally necessary part of this intrinsic pathway. And to be clear again,
with our use of arrows, this green arrow here is
different from these white arrows in the sense that here,
we are saying that fibrin is going to become fibrin strands, which is going to become
interlaced fibrin strands. So if this was all there was to the story, then every time you had
a little bit of damage to your endothelium, you would cause the extrinsic pathway to fire. So you’d create a little activated VII. You would activate some X, which would activate some
II, which is thrombin, which would start to create
fibrin from fibrinogen. And moreover, the thrombin would have this positive feedback, which would cause more and more thrombin to be produced, which would cause more and more fibrin to be produced. And basically, this
system would just spiral out of control and you would become one large walking clot. So to keep that from happening, there are some negative feedback loops. And like much of the other
steps in this picture, they are governed by thrombin. So one thing that happens
is that if thrombin helps create plasmin from plasminogen, much the way it helps create
fibrin from fibrinogen. And this plasmin acts directly
on these mesh networks of fibrin and breaks them apart. So that’s one helpful
factor, but that’s not really the example of negative
feedback because it won’t prevent the continued
production of all this. So another example is
that thrombin actually stimulates the production
of anti-thrombin, which is kind of counterintuitive, but that’s sort of
classic negative feedback. And what anti-thrombin is going to do, as you could guess, is it’s going to decrease the amount of thrombin that’s being produced from prothrombin, and it’s also going to impede the production of activated X from X. So what if this whole system didn’t work? I don’t mean the negative feedback, but I mean the whole clotting system? Well, if it didn’t work, then you wouldn’t form a stable plug here, and you would get lots of blood pouring out of your damaged endothelium. So what we call that is hemophelia. Hemo refers to blood
and phelia means love. So people who have
hemophelia, love to bleed. There are three different
kinds of hemophelia. There is A, there’s B, and there’s C. It’s easy to remember the causes of these, because A is associated with VIII. B is associated with what
comes after VIII? IX. And C is associated with
what comes after IX? Not X, actually, but XI. So we can draw those into our
clotting cascade over here to see that a factor VIII deficiency will give you hemophelia A. A factor IX deficiency
will give you hemophelia B. Whereas a factor XI deficiency will give you hemophelia C. So we see that these guys
target the intrinsic pathway.

About James Carlton

Read All Posts By James Carlton

13 thoughts on “Coagulation cascade | Human anatomy and physiology | Health & Medicine | Khan Academy

  1. I studied Robbin's pathology, I studied guyton and believe me, these 14 minutes have stood more valuable for me than those 20 pages of textbooks

  2. 13 factors all arose spontaneously in gradual evolution is quite an assumption. The first factor mutation could hardly have come post mortem after bleed out. Assuming 12 more factors had to play hopscotch for billions of years to perfect a feedback loop begs intelligent simultaneos design not random occurence. However it was an enjoyable lecture😊

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