Understanding the Blood Clotting Cascade and Proteolytic Cleavage

digestive enzymes are not the only enzymes inside our body that must be activated via the process of proteolytic

cleavage another set of enzymes found inside our body that are also activated via the process of proteolytic cleavage

are the enzymes involved in creating blood clots and the process by which we create blood clots is known as the blood

clotting cascade so let's suppose we have some type of trauma inside our blood vessel and so the endothelium of

that blood vessel basically ruptures we have a cut in our blood vessel now what begins to happen is two different

processes two different pathways begin to take place one of these pathways is a quick process and the other pathway is a

bit slower so we have the extrinsic pathway that's the quick one and we have the slightly slower one that's the

intrinsic pathway so in the extrinsic path and what happens is as a result of that cut in the blood vessel we have a

glycoprotein found in the membrane of that blood vessel that is exposed and that membrane glycoprotein the integral

the integral glycoprotein is known as tissue factor or TF so all the molecules in this diagram that are purple they're

simple proteins and in this case this is a glycoprotein the blue molecules are zymogen so basically enzymes in their

inactive form and the red molecules are the active form of enzyme so purple molecules are proteins they're not

enzymes the blue molecules are the zymogen form of the enzyme and the red molecules are the active form of that

enzyme so once we have the rupture we have the exposure of the tissue factor and basically once the TF is exposed to

the blood plasma we have this molecule that is activated so zymogen 7 is activated into its active form and this

this and then this enzyme number 7 basically binds onto the tissue factor to form and act

complex which then goes on and basically activates zymogen ten into its active form so this is basically the extrinsic

pathway an entire purpose of this extrinsic pathway is to basically create a quick response and activate this

important protein enzyme ten because it's enzyme ten after combining with another protein five that basically

activates prothrombin into thrombin and then it's thrombin that is used to actually form the blood clots that are

used to seal off that particular rupture in the blood vessel now at the same exact time to amplify to greatly

increase the number of X that we activate we also have the other pathway the intrinsic pathway and so in the

intrinsic pathway what happens is as a result of the exposure of the collagen found in the extracellular environment

outside that blood vessel so basically as a result of that cut in the blood vessel we basically create a cascade of

events we have these activation events taking place we have zymogen twelve activated to its

Enza enzyme twelve that azan twelve activates eleven inserts active form eleven then activates nine into its

active form which combines with protein eight to basically activate the same X the same enzyme ten zymogen ten that we

have in this case and so these two pathways basically converge to form this single pathway we commonly call the

final common pathway or simply the common pathway and so as a result of these two different pathways we have the

amplification the increase in the number of active X active ten enzymes that we form and so we ultimately amplify the

number of prothrombin that we activate into thrombin and once again thrombin then activates an enzyme known as

fibrinogen into fibrin and it's the fibrin that ultimately forms our blood clots

which basically looks something like this and we'll see exactly what that is in just a moment so we see that the

blood clot cascade is actually a pretty complicated cascade and actually it involves even more molecules than shown

on the board and what it also has is many different types of positive feedback loops for instance what

thrombin actually does is it not only activates fibrinogen into fibrin as we'll discuss in detail in just a moment

thrombin also creates many different positive feedback loops so it actually moves on to many of these zymogens and

it further activates those imagens into their active form and what these different positive feedbacks loop do is

they further amplify the number of thrombin that we actually form so that what happens is as soon as we have that

rupture we form many of these blood clots very quickly and very effectively so that none of that blood plasma

actually leaks out into the extracellular environment found outside that blood vessel that we can actually

see law of that rupture very quickly and very effectively so once again when blood vessels experience trauma and

rupture our body uses over a dozen different enzymes and proteins to create a cascade of events that ultimately

forms blood clots that are used to seal off that particular cut in that blood vessel and again we have these blue

molecules these are the zymogen enzymes then we have the red ones those are the active form of that zymogen and the

purple molecules these molecules are basically proteins they're not enzymes they're proteins involved in actually

assisting this cascade of events so we have the extrinsic and intrinsic pathway which basically work together to amplify

the number of protein or enzyme acts that we produce which ultimately then follows the final common pathway so the

extrinsic and intrinsic pathway basically converge into the final common pathway that ultimately forms and

activates thrombin which then goes on to activate fibrinogen into fibrin so blood clots are form via series of zymogen

activations this cascade consists of the extrinsic and the intrinsic pathway that work together to amplify the activation

of an important serum protease known as thrombin and thrombomodulin eclis activate fibrinogen which then basically

forms these aggregates we call fibrin molecules which consists of this mesh like network that is used to actually

seal off that particular clot so these are not that particular cut and these are known as blood clots now in addition

what we don't show is these many different types of positive feedback loops that we also have in this

particular cascade as i mentioned earlier for instance we have throb and that creates many different types of

positive loops and so it goes back to many of these zymogens and it basically activates the zymogen x' even further so

that ultimately we amplify the number of blood clots that we form at the end so in addition thrombin creates many

positive feedback loops that further amplifies the formation of the blood clots now as we see we have many

examples of zymogen so we have this is a zymogen this is a zymogen these are zymogen and so forth now the zymogen

that we actually studied very well is this signage in here so this is the zymogen that we're going

to study we're going to see how thrombin a serine protease basically activates fibrous fibrinogen proteolytically into

fibrin and fibrinogen actually activates fibrinogen so this is basically the structure of a single fibrinogen

molecule know is we have many different sections in fact we have six chains two of these

chains consist of the purple a and lowercase alpha two of these chains consist of the blue B and the beta chain

the orange one and two of these are our gamma so the green one so we have these green those are the gamma we have these

are the orange ones those are the beta we have these light blue ones those are the B's we have these purple uppercase

A's and then we have these red lowercase alphas and so we have many different chains found in a single fibrinogen

molecule so this molecule is in its inactive form this is the zymogen form of this molecule now what exactly does

throb and actually do so the entire goal of the extrinsic pathway and the intrinsic pathway is to basically

amplify and activate this protein X protein 10 and the enzyme 10 basically combines with five to go on and form

thrombin from the zymogen form prothrombin now thrombin is actually a serine protease and it will activate

this fibrinogen molecule proteolytically and what it does is it Cleaves at four different locations so what are these

four locations so right here right here right here and right here and this is shown in the following diagram so

essentially the active thrombin goes on and Cleaves at these four locations and what that does is it completely removes

these to be chains and these two a chains and these four individual chains once they are removed we call them five

Breno peptides and so we remove these four fibrin apep tides and what we form is is a single active fibrin monomer so

this is basically what it looks like so we remove these four chains and we form the following active fibrin monomer so

monomers simply means we have a single fibrin molecule in its active form so thrombin

is a serine protease that uses proteolytic activation to activate fibrinogen this molecule and the way

that it activates it is by cleaving at four different sites on that molecule and by cleaving at least four different

sites we basically form four in the or we basically remove four different peptides and these four peptides are

shown here these are known as five Greenough peptides and what we ultimately form is a fibrin monomer that

consists of these three different subunits so alpha B and gamma and we have twice the number of these so these

are the two of our the B not the so that should actually be not a B but a beta so this should be a beta so we have two of

these orange betas we have two of these green gammas and then we have these red alphas and we basically removed these

purple a's and those blue B's now once we form the fibrin monomer what exactly happens next well by cleaving and

removing these two sections and these two sections we basically expose a very important section of that fibrin

molecule and because we expose that section of our fiber and it activates that fibrin and so one fibrin monomer

will basically go on and interact with another fibrin monomer and this process will continue until we basically form

this very long mesh like structure and aggregate we call the fibrin or simply the blood clot and this is basically

what it looks like so the proteolytic cleavage of fibrinogen exposes regions of the structure that can interact with

other fibrin monomers therefore fibrin monomers spontaneously aggregate to form long fibers straw

is called fibrin so we have the aggregation of these fibrin monomers because now these sections here are

basically exposed and these sections found on the alpha unit the red one can basically interact and fit into these

holes found on the green structures those gamma units and so this is basically what we form so we have these

red structures found on the Alpha that interact with the blue hole above the the green structures the holes found in

the green structures those gamma structures and so we form this mesh like structure this mesh like network of

fibrin monomers and we call this entire structure fibrin or blood clots and these blood clots can basically

aggregate right across that rupture and that seals off that rub drip so we have the polymerization of fibrin monomers

that forms blood clots that can seal off the ruptures that form as a result of that trauma so we see that not only

digestive enzymes are activated via the process of proteolytic cleavage these enzymes that are part of the blood clot

cascade are also activated via the process of proteolytic cleavage and we see that proteolytic activation is a

very dominant mechanism here because essentially the majority of all these different dimensions are activated via

the process of proteolytic cleavage so we have these images the blue ones here these dimensions here as well as the

main zymogen the prothrombin which basically is active into the thrombin and that goes on to activate the

fibrinogen into fibrin which ultimately forms those blood clots those mesh like networks of fibrin monomers that

essentially seal off and prevent the leaking of the blood plasma from within that blood vessel and into the

extracellular man found around that blood vessel