00:01
Hello, and welcome to
Thrombotic Disorders.
00:03
In this section, we're gonna be forming
too many thrombi pathologically.
00:08
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.
00:23
Now, in this picture...
00:25
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.
00:38
Therefore, there's no need for
thrombi formation to take place.
00:44
In the picture,
the topic is fibrinolysis.
00:50
In the picture, it represents the
different ways physiologically
where we control the amount
of thrombi being formed.
00:59
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.
01:16
Normally, that thrombin is
broken down by antithrombin.
01:22
Specifically,
antithrombin III...
01:24
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.
01:38
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.
01:49
So in other words,
I'm going to have thrombophilia for you.
01:55
For example, let's take a look
at number two in the red circle.
01:59
It is the second most common
hereditary thrombophilia.
02:05
Notice, I said thrombophilia.
02:07
Too much, phillia means too
much, but too much what?
Thrombi formation.
02:13
Whereas hemophilia would
be too much bleeding.
02:18
But what happened here?
So this is a mutation that
takes place specifically,
you must be able
to identify 20210A.
02:29
And what then that represents would then
be your nucleotides as we shall see.
02:36
For example, when we talk about A as being
a nucleotide, then that would be adenine.
02:41
A mutation taking place in what
is known as guanine and adenine,
resulting in increased stability
of the prothrombin mRNA.
02:48
By the way, the mutation does not affect
the prothrombin protein itself in any way
because the mutation is
in a non-coding region.
02:56
The mutation results in over
translation of the prothrombin gene,
which then results in
hyperprothrombinemia.
03:02
The hyperprothrombinemia puts the patient
at an increased risk of thrombosis.
03:07
Guess in what state
this patient is in?
Hypercoagulable, in other
words, thrombophilia.
03:14
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.
03:36
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.
03:58
I bring all this to your
attention, why?
Well, some of that protein that
may be lost in nephrotic syndrome
could be antithrombin III.
04:08
Now, picture that.
04:10
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.
04:25
Now, would you call this
acquired or congenital?
Acquired, the nephrotic then caused an
acquired type of hypercoagulability.
04:35
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.
04:49
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.
05:05
So now that you've gotten a general picture
of how this is organized, let's continue.
05:11
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
the proteolysis of factor V.
05:19
Yes, you also see factor VIII but
I want you focus at this point
at proteolysis of factor V.
05:26
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.
05:43
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.
05:54
Well, when protein C
and S get together,
they then neutralize
and proteolyze factor V.
06:02
Now, this then brings us
to are the most important
and the most common
hereditary thrombophilia
which is then called
factor V Leiden.
06:13
Take a look at number one.
06:15
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.
06:37
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.
06:53
In other words, it is resistant to
the cleavage of protein C and S.
06:58
So guess what your patient
is presenting with?
Recurrent DVTs, hypercoagulable.
07:05
Let's continue.
07:07
What if you had a patient who
is deficient of protein C and S?
Well, to begin with, you know
protein C and S or anticoagulants,
you know they're vitamin
K dependent factors.
07:17
We've had the discussion where the
half-life of C and S is extremely short.
07:22
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.
07:31
So here once again,
you would be in a hypercoagulable state.
07:35
Now, these are the major
pathologies of hypercoagulability
either in the form of
congenital or acquired.
07:43
The most common, hereditary,
would then be factor V Leiden.
07:48
The second most common
would be prothrombin 20210.
07:52
And then we talked about deficiency
of antithrombin III acquired type
or a lack of protein C and S.
07:59
Now, in the picture itself,
there are a couple of other things
that I need to bring to
your attention please.
08:04
Here, you're gonna focus on the
tissue factor pathway inhibitor.
08:08
There's a lot of
research on that.
08:10
The tissue factor earlier we've talked
about in the coagulation cascade
in which it helps you activate factor
VII, the extrinsic system.
08:18
Do you remember that?
So here we have a tissue
factor pathway inhibitor.
08:24
So guess which factor
it's going to inhibit?
Voila!
Factor VII, there you have it.
08:31
I want us to take a
look at something else.
08:34
Remember,
it's all about that seesaw.
08:35
In other words, homeostasis.
08:38
We just had thrombi formation.
08:40
There's signaling taking place, ha!
And thrombi is now done with its job.
08:45
The objective has been reached.
08:47
So now I need to break
down the thrombin.
08:50
So thrombin itself if you
take a look will then bind to
with something called
thrombomodulin.
08:56
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.
09:10
Then from the endothelial cells,
now, let me ask you something.
09:14
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.
09:30
Now, that I have an endothelial
cell, I don't wanna form a clot.
09:34
I just wanna go with life as being
perfectly normal without any disruptions.
09:40
So, therefore, the endothelial
cell will for something that's the
opposite of thromboxane.
09:46
Welcome to, take a look,
from the endothelial cells,
we have Prostacyclin,
we have Nitric oxide, and ADPase.
09:57
Not ADP.
09:58
Remember,
what activated the platelet? ADP.
10:03
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.
10:18
If you block the ADP,
the ADP never activated the platelet.
10:23
Endothelial cell is going
to produce an enzyme
to cleave the ADP
making it null and void.
10:31
And then finally, you have tissue
plasminogen activator, right?
So Tissue plasminogen activator obviously
here, I don't want thrombin or fibrin.
10:40
I would like there to be
something to break down my clot.
10:44
Welcome to TPA.