Understanding Hemophilia A: The Most Common Bleeding Disorder

the most common bleeding disorder in humans is hemophilia a also known as classic hemophilia now before we discuss

this medical condition and before we actually discuss what causes it let's remember the blood clot in Cascade and

what it actually is well whenever there's some type of trauma inside our blood vessels so for example we have a

cut or we have some type of rupture in the endothelium of a blood vessel in our cardiovascular system that basically

initiates the blood clot and Cascade and what the blood clot and Cascade is and what it does is so it basically consists

of these many proteins and enzymes that work together to coordinate the formation of blood clots and these blood

clots are basically meshlike networks of these individual fibrin molecules that basically create the meshlike structure

that ultimately forms the blood clots and these blood clots can basically coag at and they can seal off that rupture

that cut and that prevents the leakage of blood out of that blood vessel and into that surrounding tissue now if we

actually examine the blood clot in Cascade we'll see that there are two important Pathways we have the extrinsic

pathway and we have the intrinsic pathway so let's begin by focusing briefly on the extrinsic pathway so in

the extrinsic pathway what happens is once we have the cut in the endothelium of the blood vessel that exposes an

important integral glycoprotein that wasn't there before and this is known as TF which stands for tissue Factor now

everything shown in this diagram that is purple that basically describes a protein that is not an enzyme and so the

tissue factor is not an actual enzyme it's simply a glycoprotein that exists on the membrane of the Endo of the

endothelium now once this is exposed inside the blood plasma we have this zymogen we call Factor 7 and once this

is exposed Factor 7 is basically activated via proteolytic cleavage and once we activate Factor 7 it goes on it

interacts and binds to the tissue factor to form a dimer complex and then the dimer complex it interacts with a very

important factor uh Factor X Factor 10 to basically proteolytically cleave it and activate it into its active form so

the red one is the active form of factor 10 so everything shown in blue is an enzyme but it exists in a xymogen in

active form the red molecules are those enzymes in their fully active form so blue means inactive zymogen and red

means fully active and so once these two interact they go on to activate this one into its full fully functional and

active Factor 10 now once we form factor 10 Factor 10 basically combines and interacts with another protein called

Factor five and once they form that complex that basically goes on and activates another important molecule we

call prothombin and this is what we spoke of earlier so basically prothombin is activated so thrombin and then and

then it's this thrombin that basically goes on Via the commet pathway or the final commet Pathway to ultimately form

this meshlike network of fibrin we call blood clots because thrombin activates fibrinogen into fibin monomers and the

and then these fibin monomers basically aggregate they they form these clusters that form our blood clots now thrombin

is also important because it actually goes back and creates many different positive feedback loops as we'll see in

just a moment and that amplifies the effect now let's look at the intrinsic pathway because ultimately it's the

intrinsic pathway that is affected by this medical condition we call hemophilia a so in the intrinsic pathway

following the exposure of the surrounding tissue following that cut in the blood vessel that basically

stimulates the the proteolytic activation of factor 12 and then once Factor 12 is activated it goes on to

proteolytically activate Factor 11 and that goes on to proteolytically activate Factor 9 now Factor 9 cannot by itself

activate Factor 10 what must happen is this uh protein that is not an enzyme so factor eight basically interacts and

stimulates this Factor 9 to go on and activate Factor 10 and so ultimately what we see is this is the converging

point of these two Pathways and these two Pathways basically ultimately do the same exact thing they basically activate

Factor 10 which is needed to basically initiate the final Comon pathway that is needed to actually stimulate the

activation of thrombin which is then used to stimulate the activation of fibrin and these fibin molecules

basically form this mesh like aggregate so these are the individual firein monomers and they basically aggregate

spontaneously following activation to form our blood clot and the blood clot is used to basically coagulate the blood

to form those clots on those cuts to basically prevent the leakage of blood out of that blood vessel now as I

mentioned earlier thrombin basically creates various different types of feedback loops and one one of these

positive feedback loops is shown on the board with the green arrow so what happens is once throbin is activated it

not only activates fibrinogen to form fibrin it also goes back and stimulates factor 8 to basically continue to

interact with Factor 9 to basically stimulate or to basically convert even more of these factor x inactive Zog and

Factor 10 into the ACT form and so these two Pathways along with all these different types of positive feedback

lose basically greatly amplify the number of blood clots that we form and so what happen is because of the

quickness and the efficiency of this blood clot and Cascade as a result of the correct functioning of all these

different proteins and enzymes and Pathways were actually able to actually quickly seal off that cut that rupture

in the blood vessel now what happens in hemophilia is as I mentioned earlier it's the intrinsic pathway that is

actually impeded that is actually affected and to be more specific it's factor a that is affected as a result of

Hemophilia and that's exactly why factor 8 is also commonly known as the antihemophilic factor and that's because

if this antihemophilic factor is actually present and functions correctly inside our body then that will prevent

hemophilia a also known as classic hemophilia so factor 8 is a protein that plays The crucial role in the intrinsic

pathway of the blood clot and Cascade and there are two important roles as we discussed just a moment ago so role

number one is it actually plays an important role in actually completing the intrinsic pathway so we see that at

the final step of the intrinsic pathway way it's this antihemophilic factor factor a that must stimulate interact

with this factor nine to basically go on and convert the xogen factor 10 form into its active form now if this

molecule is destroyed if there's some type of mutation or if it's missing all together then this will not be

stimulated and will not be able to actually activate this Factor 10 and so if that doesn't take place that the

entire intrinsic pathway basically slows down its impaired and what that means is we will not amplify the effects the

formation of the blood clots we're not going to be able to form as many blood clots as we want we're not going to be

able to form them quickly enough and so that will result in excessive bleeding now the other reason why the impairment

of this factor a is so uh so negative is because thren actually uses this to create a very important positive

feedback loop as we discussed just a moment ago so thrombin essentially depends on factor eight on the presence

of factor eight to create the positive feedback loop that greatly amplifies the number of factor 10 that we actually

activate and that in turn amplifies how much of the blood clots we actually can form how many of the blood clots we can

form so two important functions of factor 8 factor 8 interacts with proteolytic

enzyme Factor 9 and stimulates it to basically go on and activate Factor 10 which is needed to ultimately coagulate

the blood and form the blood clots because it's this molecule Factor 10 that initiates the final common pathway

that is used to form those blood clots and the second important function of factor eight is

uh thrombin creates a positive feedback loop stimulating factor eight swimming around in the blood to interact with

factor nine which causes an amplification effect and this is basically this positive feedback loop

that I just discussed just a moment ago so we basically see that in individuals with classic chilia there's some type of

mutation in factor 8 or in some cases factor8 is missing entirely and so what that means is the impairment of factor 8

greatly impedes this process the intrinsic pathway and if the intrinsic pathway does not function properly we

cannot amplify we cannot create these blood clots quickly enough and so what that means is once the blood vessel

actually is cut once the endothelium ruptures the blood clots do not form at a high enough rate and so

excessive bleeding may occur and this is exactly why hemophilia a is a bleeding Disorder so an individuals with

hemophilia a when they essentially CL when they essentially cut a blood vessel this is basically what takes place and

this is why it actually takes place and the final thing I'd like to mention is as you might know from basic biology

hemophilia a is actually a sexlink recessive trait and that's exactly why male indiv indviduals basically are

those that have an Express the hemophilia a because it's a sexlink recessive trait if an individual that is

a female contains a a u one dominant trait and one recessive trait that dominant trait will basically overpower

that recessive trait and so a heterozygous female individual even though she will be a carrier she will

not actually Express this medical condition because because she will have the gene to actually produce that fully

functional uh factor 8 antihemophilic Factor protein that is actually responsible for finishing off that

intrinsic pathway