Understanding Hemorrhage and Thrombosis: The Role of the Coagulation Cascade

when a blood vessel of our cardiovascular system is injured for instance we have a rupture in the wall

of that blood vessel the process of hemorrhage will take place and hemorrhage is the medical condition that

describes the process by which blood escapes out of the cardiovascular system and into the surrounding area found

outside the blood vessel now hemorrhage can be very dangerous it can cause damage to the tissues and organs of our

body and so to prevent hemorrhage from actually taking place and causing damage we have the blood clotting cascade that

is immediately initiated and when the blood clotting cascade is initiated we produce these blood clots and the blood

clots are used to create temporary seals along that area where the cut actually exists on that blood vessel so we know

that blood clots can be very very beneficial but on the other hand if we form too many blood clots or if we can

break down the blood clots properly or if those blood clots escape that localized area where that injury took

place that can lead to many many problems now one problem is thrombosis so thrombosis is basically the process

by which we form the blood clots and if these blood clots are formed excessively they can basically escape into the

cardiovascular system and eventually they can aggregate at the wrong place and that can block the flow of blood and

this is known as an embolism so an embolism is the process by which these abnormally or these blood clots

aggregate abnormally and they block that flow of blood to some areas some tissue of some organ of our body and that can

lead to many problems for instance if we have an embolism that takes place in the coronary artery that can lead to a heart

attack and obviously a heart attack is very very dangerous so there is a very very fine line

between thrombosis and hemorrhage and to prevent either one of these from taking place and damaging our organs and

tissues our body must be able to very precisely and very effectively regulate the coagulation cascade and so

previously we discuss the activation of this process now we're going to discuss the inhibition so how exactly do we down

regulate and inhibit the different enzymes involved in the coagulation cascade process so this is what we're

going to focus on in this lecture and we're going to discuss several important key factors that inhibit the enzymes

that are part of the coagulation cascade so let's begin with the molecule known as tissue factor pathway inhibitor or

simply T F P I now this is a polypeptide and what the polypeptide does is it ultimately binds unto a complex that is

part of the extrinsic pathway of the blood clotting cascade so if we think back to the blood clotting cascade we

have these two different pathways we have the intrinsic and the extrinsic pathway and this polypeptide blocks

essentially that extrinsic pathway from taking place so in the extrinsic pathway we have the tissue factor the

glycoprotein found on the membrane of the endothelium of the blood vessel basically forms a dimer complex with

factor 7 and once we form this complex this complex then reacts with fact the turn to basically activate it and begin

the final common pathway now what the tissue factor pathway duh what the tissue factor pathway inhibitor does is

it binds unto the tissue factor factor 7 complex and it inhibits its activity and it also has domains on this polypeptide

that can bind onto the individual effector 7 and that factor 10th and it can inhibit both of these different

molecules now what about our intrinsic pathway so let's take a look at protein C protein C is a vitamin K dependent

protease and what that means is it depends on the presence of vitamin K to actually affect them correctly to

actually function correctly and effectively so if we don't have vitamin K if we have a vitamin K deficiency in

our body that will basically mean that protein C cannot actually function properly

now protease basically means when it acts with its target molecule it hydrolyzes it breaks the peptide bonds

at specific sites on the target molecule so protein c is a protease meaning it digests it's its target molecule so

protein C interestingly is actually activated by thrombin and thrombomodulin form fibrin from fibrinogen and fibrin

is used to form the blood clots so thrombin has a dual purpose it not only actually forms the blood

clots but it also is responsible for inhibiting the coagulation process by activating protein c because what

protein c does is it breaks down and digests two important stimulating proteins part of that coagulation

cascade namely factor v and factor 8 now factor 5 if we remember from the previous several lectures is basically

that stimulating protein that binds onto factor 10 and that activates thrombin on the other hand we have factor aid which

is also known as the anti hemophilic factor and this is responsible for binding onto factor 9 which activates

fact attendant to its active form so protein c is responsible for essentially inhibiting the intrinsic pathway while

tissue factor pathway inhibitor is responsible for inhibiting the extrinsic pathway so now let's take a look at

another important molecule that acts as an irreversible inhibitor to thrombin and this is antithrombin 3 so anti

throbbin 3 is a glycoprotein whose structure actually resembles structure of an inhibitor we spoke about

previously alpha-1 antitrypsin so if you remember alpha 1-antitrypsin is that irreversible

inhibitor that inhibits elastase as well as trypsin well in a same exact way anti antithrombin 3 basically binds to the

active side and inhibits the activity of thrombin and by inhibiting thrombin we basically inhibit the final common

pathway and we inhibit the formation of blood clots now antithrombin 3 can also form

complexes with many other factors so if we think back to the intrinsic pathway we know that intrinsic pathway contains

fat the 12 fact 11 factor 9 and these 3 factors can also be inhibited by antithrombin 3 and antithrombin 3 can

also inhibit factor 10 which is basically that converging point between the extrinsic and intrinsic pathway it's

the beginning of that final common pathway so we see that antithrombin 3 is a glycoprotein that resembles the

structure of alpha 1-antitrypsin now it binds with very high affinity to thrombin and it activates its activity

and in also blocks it forms complexes with other factors of the intrinsic pathway and the final common pathway so

we have factor 12 we have factor 11 and we have factor 9 that are part of the trinsic pathway and then we have the

fact that 10 which is basically the initiation of the final common pathway it's that fact that that is part of that

converging point between the intrinsic and the extrinsic pathway now let's move on to heparin and heparin Co factor 2 so

heparin cofactor to is actually a molecule that enhances that tivity of heparin so let's begin by discussing

what heparin actually is so if we examine the connective tissue found surrounding our blood vessels

- fine immune cells known as mast cell so mast cells are these immune cells part of our adaptive immune system which

basically release an important glycosaminoglycan known as heparin and heparin is this negatively charged

glycosaminoglycan that basically enhances the activity of antithrombin 3 it stimulates antithrombin 3 to

basically form these irreversible inhibited complexes with not only thrombin but all these other factors so

factor 12 fact 11 factor 10 and factor 9 so heparin acts as an anticoagulant by stimulating the binding of antithrombin

3 to thrombin and the other serum proteases these ones that we mentioned just a moment ago now what do we mean by

an anticoagulant well the process of coagulation means to form the blood clot so anticoagulation means to not form the

blood clots and that's exactly what the heparin does it stimulates antithrombin 3 to basically inhibit the activity of

robbing which means we cannot form those blood clots and as I mentioned a moment ago heparin is or heparin cofac the two

is basically this protein that floats around our plasma the blood plasma and it basically assists heparin to

basically bind onto the antithrombin 3 to inactivate inhibit the activity of thrombin so everything we spoke about up

to this point basically involved actually inhibiting these specific enzymes and proteins that are found

within the coagulation cascade but the next question is once we actually form those blood clots once we actually form

those fibrin mesh like structures we call blood clots that actually seals off and creates that temporary protective

layer that prevents hemorrhage what actually happens to the blood clots once the cell is actually once the cells

actually that ruptured area in that blood vessel so blood clots are temporary solutions

to sealing offerors in the blood vessels and once those ruptures are fixed by the cells of our body how exactly does our

body actually remove and digest these blood clots because these blood glue of these blood clots must actually be

hydrolyzed digested and broken down by the cells of our body well we have the function of a very important protease

serine protease known as plasma so plasma is basically this serine protease that once activated it finds it locates

these fibrin molecules and in hydrolyzes those fibrin molecules into smaller pieces and those smaller pieces dissolve

into our blood plasma and they travel to the liver and the liver cells basically hydrolyze and break down these even

further and then different components are basically recycled by ourself now plasmon like most of these different

enzymes involved in the coagulation cascade initially exist in there in active precursor zymogen form and the

zymogen of plasma is plasminogen so plasminogen is activated by another molecule known as tissue type

plasminogen activator so TPA so essentially plasminogen is a zymogen and inactive form of plasmid that has a

very high affinity for fire band but before actually becomes active it must be activated by tissue type as mijin

activated TPA and once TPA activates plasminogen to plasmin then locates that blood clot that consists of those fibrin

molecules and it Cleaves it breaks the peptide bonds in those fibrin molecules and then the five brand molecule was

basically the sociate from that blood vessel wall and they travel to the liver cell and the liver cells essentially

digest and recycled those blood clots so plasma is in protease which is responsible for

actually breaking down and digesting those blood clots and that ultimately prevents the process of thrombosis from

actually taking place for instance if we examine individual that basically develops an embolism in the coronary

artery so essentially if we give an individual that is experiencing a heart attack the tissue type plasminogen

activator if we inject it into the blood of that individual what happens is this tissue type plasminogen activator

initiates these plasma molecules so activates transforms the plasminogen to plasmin and and what plasma does is

plasma moves into that coronary artery of the heart of that individual experiencing the heart attack and it

basically begins to break down the blood clot that is formed as a result of that embolism and so by giving an individual

who is experiencing heart attack the tissue type plasminogen activator that greatly increases the likelihood that

individual will actually survive that heart attack so we can see that these different molecules can be used for

medicinal purposes in many different ways but generally speaking because there is this very fine line between

thrombosis which is basically the formation of the blood clots and hemorrhage which is the process by which

blood leaks out of the blood vessels because there's a very fine line between these two processes our body must be

able to actually not only activate the coagulation cascade process but also inhibited and so these are the different

molecules that are basically used to control and inhibit that tivity the formation of the blood clots the

activity of the coagulation cascade