00:00
So with all of these different things, we got the intrinsic,
the extrinsic pathway, what's
really the major pathway if I have vascular injury, I've cut
my finger and it needs to stop
bleeding. It's usually mainly the extrinsic cascade that
drives that real true coagulation and
it's the exposure to tissue factor that occurs when I have
injury. So it's the extrinsic
pathway and vascular damage. So that vascular damage exposes
thromboplastin, otherwise
known as factor III otherwise known as tissue factor. And
that tissue factor interacts with
factor VII, make it a complex now with activated factor VIIa
and tissue factor and we get
to the common pathway and then we get into the activation of
prothrombin to thrombin
fibrinogen being crosslinked and there you have it. That's
the extrinsic pathway. Now,
why then do we have all those other things on the left hand
side? Why do we have the
intrinsic pathway? Well, it turns out that they get brought
into the game through the
activity of prothrombin or thrombin. Okay, so the tissue
factor, factor VII, the red box
there drives extrinsic pathway to activate thrombin but the
same factors are also feeding
back. So we have VIIa again in our extrinsic pathway that
crosses over into the intrinsic
pathway to activate IX to IXa and get us into the common
pathway so we can get an
amplification. Notably, you see here that VIIa activating IX
to IXa completely bypasses the
original involvement of XII. And it turns out that you can
be completely totally deficient in
factor XII and have completely normal coagulation that's
because of this kind of bypass
pathway that gets us from extrinsic to intrinsic. Okay,
remember I said that thrombin is also
acting back on all those pathways. In fact, not only is it
driving fibrinogen to be cleaved to
become fibrin and giving us a clot, at the same time it's
feeding back. And you see these
dotted red lines, these are inhibitory pathways where
thrombin is going to be acting on
these important cofactors or other pathways to cause other
proteolytic cleavages that will
inactivate. So thrombin, major linchpin, it drives both
coagulation and also helps to
regulate that coagulation so we don't clot off the entire
arm when we cut our finger.
02:45
So, thrombin, also known as activated factor II, cleaves
factors V, VIII, XI, and XIII. Some of that
is procoagulant, some of that is anticoagulant. So thrombin
is much more than just the step
before fibrin. The other thing that it does is that it
activates a whole variety of other
pathways and then we're going to bring those up now. So
thrombin will interact with a
specific receptor. It's called PAR1, stands for the
proteolysis activated receptor 1. It's on a
variety of cells, we'll see what cells in a minute. But
interestingly, it's not just thrombin
binding to that receptor. It actually binds and cleaves that
receptor so that we now get
an activated molecule that autostimulates itself. Wow,
that's going to be incredibly a problem
because it really doesn't go away very much. Okay, so
thrombin now has cleaved that. It
turns on itself, binds, and activates. And what is it
activating? So here we have thrombin
acting on platelets. It will drive platelet aggregation and
the release of granules. So we
produced thromboxane A2 so we can drive improved platelet
clotting. It will also act on
endothelial cells. Those endothelial cells are going to be
making a variety of things such as
nitric oxide, prostaglandin II otherwise known as
prostacyclin and tPA. And these are
going to tend to be antithrombotic. They're going to tend to
start the feedback in addition
of a whole thrombotic cascade, and we'll talk more about
those in a subsequent session.
04:34
Thrombin will also activate lymphocytes. Makes sense
actually. You really want in an area of
injury to have the immune system also called in to do their
thing. It will drive endothelial
cells to monocytes to make platelet-derived growth factor.
Although it's called platelet-
derived growth factor, we now know that it's made by a
variety of cell types including in this
case endothelium and monocytes. That PDGF synthesized by
those cells driven by thrombin
will act on smooth muscle cells. Also makes sense because
the smooth muscle cells around
the vessel will also probably had been injured in the
process and we need to drive their
proliferation to provide healing for the blood vessel.
Thrombin will also induce increased
neutrophils adhesion. Again makes sense because in an area
of injury we want to bring in
the innate immune response. So thrombin is doing a whole lot
more than just driving
fibrinogen to become fibrin. It is doing a whole ride of
activities including counterregulating
the aggregation thrombosis response. And with that, we
conclude the coagulation factors.