Hello, and welcome to thrombotic disorders.
In this section, we're gonna be forming too many thrombi pathologically.
And just like we had done earlier where we had bleeding diathesis
and we approached in organized fashion,
we'll be doing the same thing here as well so that this never leaves you.
Now, in this picture, the job of the thrombi has been completed, okay?
In this picture, you'll notice the cells on the top, in the picture
and the cells on the bottom represent intact endothelial cells.
Therefore, there's no need for thrombi formation to take place.
In the picture, the topic is fibrinolysis.
In the picture, it represents the different ways physiologically
where we control the amount of thrombi being formed.
For example, if you take a look at thrombin in the picture,
it normally as we said will cleave the fibrinogen forming fibrin,
forming a stabilized platelet plug.
Normally, that thrombin is broken down by antithrombin.
Specifically, antithrombin three and therefore,
regulating the amount of thrombi that's being formed, correct?
We also talked about drugs such as heparin
which worked through antithrombin III so that we could have bleeding.
Now, if the picture then represents bleeding,
then what you'll see here in pathologies
and the differentials are those pathologies that result in thrombi formation.
So in other words, I'm going to have thrombophilia for you.
For example, let's take a look at number two in the red circle.
It is the second most common hereditary thrombophilia.
Notice, I said thrombophilia.
Too much, phillia means too much, but too much what?
Whereas hemophilia would be too much bleeding but what happened here?
So this is a mutation that takes place specifically, you must be able to identify 20210A.
And what then that represents would then be your nucleotides as we shall see.
For example, when we talk about A as being a nucleotide, then that would be adenine.
And there would be a mutation taking place in what is known as guanine and adenine,
resulting in increased stability of the prothrombin mRNA. By the way,
the mutation does not affect the prothrombin protein itself in any way because
the mutation is in a non-coding region. The mutation results in over translation
of the prothrombin gene, which then results in hyperprothrombinemia.
The hyperprothrombinemia puts the patient at an increased risk of thrombosis.
Guess in what state this patient is in? Hypercoagulable. In other words, thrombophilia.
Or for example, a very commonly asked or should I say
a situation that commonly is presented to you will be one in which let's say that
in the urine of this particular patient,
you might find frothy urine or it looks like bubble urine.
Whenever you hear the word frothy or bubbly type of urine, you should be thinking,
Oh, that's a lot of protein loss, isn't there?
Now, of the two categories of nephritic and nephrotic,
which one of those categories represents more of an increase in protein loss?
Obviously, the nephrotic syndrome greater than three and a half grams of protein per day.
I bring all this to your attention, why?
Well, some of that protein that may be lost in nephrotic syndrome could be antithrombin III.
Now, picture that.
So if antithrombin III normally knocks out the thrombin so that I don't have thrombi formation
or I control thrombi formation, what if we lose antithrombin III?
You lose antithrombin III, there's nothing stopping my thrombi.
Now, would you call this acquired or congenital?
The nephrotic then caused an acquired type of hypercoagulability.
Take a look at the circle where it says number three in under antithrombin III deficiency in the list,
you'll be focusing on acquired and specifically, nephrotic syndrome.
Could you lose other coagulation factors and such?
Maybe, but in nephrotic syndrome, 5 to 10% of the time,
your patients may present with hypercoagulability in nephrotic syndrome.
Keep that in mind.
Or congenitally, you could be losing also antithrombin III.
So now that you've gotten a general picture of how this is organized, let's continue.
I want us to know or I want you to take a look at and focus on the proteolysis of factor V.
Yes, you also see factor VIII but I want you to focus at this point the proteolysis of factor V.
So what does factor V do?
Well, factor V helps to stabilize let's say factor X to help then form the prothrombin complex, right?
So once you do, then, you're gonna form a thrombi
but in this picture as I said, we're breaking down our thrombi.
So what is or what are the proteins responsible for breaking down that factor V?
Here, we have protein C and protein S, you group those together.
Well, when protein C and S get together, they then neutralize and proteolyze factor V.
Now, this then brings us to... are the most important and the most common hereditary thrombophilia
which is then called factor V Leiden.
Take a look at number one.
So what happens in factor V Leiden?
In factor V Leiden, I'm gonna give you a young lady and she has recurrent DVTs
and you come to find out later on that she has a mutation taking place with a, well,
you have an issue with your glutamine to arginine mutation.
The glutamine to arginine mutation taking place at position
let's say 506 results in a condition called factor V Leiden
in which that factor V normally being cleaved by protein C and S is no longer taking place.
In other words, it is resistant to the cleavage of protein C and S.
So guess what your patient is presenting with?
Recurrent DVTs, hypercoagulable.
What if you had a patient who is deficient of protein C and S.
Well, to begin with, you know protein C and S are anticoagulants.
You know they're vitamin K dependent factors.
We've had the discussion where the half-life of C and S is extremely short.
In addition, if you're deficient of protein C and S,
then what you have circulating in your body would be more or less your thrombotic factors.
So here once again, you would be in a hypercoagulable state.
Now, these are the major pathologies of hypercoagulability either in the form of congenital or acquired.
The most common, hereditary, would then be factor V Leiden.
The second most common would be prothrombin 20210.
And then we talked about deficiency of antithrombin III acquired type or a lack of protein C and S.
Now, in the picture itself, there are a couple of other things that I need to bring to your attention please.
Here, you're gonna focus on the tissue factor pathway inhibitor.
There's a lot of research on that.
The tissue factor earlier we've talked about in the
coagulation cascade in which it helps you activate factor VII, the extrinsic system.
Do you remember that?
So here we have a tissue factor pathway inhibitor.
So guess which factor it's going to inhibit?
Viola! Factor VII, there you have it.
I want us to take a look at something else.
Remember, it's all about that seesaw.
In other words, homeostasis.
We just had thrombi formation.
There's signaling taking place, ha!
And thrombi is now done with its job.
The objective has been reached.
So now I need to break down the thrombin.
So thrombin itself if you take a look will then bind to with something called thrombomodulin.
And the thrombomodulin will modulate the thrombin,
so then, it could activate the proteins C and S which ultimately
is then, going to help you break down factor V and technically, factor VIII as well.
Then from the endothelial cells, now, let me ask you something.
If the platelet was responsible for forming a clot, right?
If the platelet in its primary objective in life as a platelet
was to form a clot, then, I wanna form thromboxane.
Now, that I have an endothelial cell,
I don't wanna form a clot.
I just wanna go with life as being perfectly normal without any disruptions.
So, therefore, the endothelial cell will for something that's the opposite of thromboxane.
Welcome to, take a look, from the endothelial cells,
we have Prostacyclin, we have Nitric oxide, and ADPase.
Remember, what activated the platelet? ADP.
What was the name of that drug or the classification of drugs
that inhibited the ADP from activating the platelet?
Remember those drugs that had the letters GREL in them?
They were P2Y12 receptor antagonists.
If you block the ADP, the ADP never activated the platelet.
Endothelial cell is going to produce an enzyme to cleave the ADP making it null and void.
And then finally, you have tissue plasminogen activator, right?
So Tissue plasminogen activator obviously here,
I don't want thrombin or fibrin.
I would like there to be something to break down my clot.
Welcome to TPA.