Here we’ll take a look at two mechanisms of anticoagulation, two.
The first one would be once again a direct acting thrombin inhibitor or thrombin inhibitors
and the other one would be the warfarin or a.k.a., Coumadin.
We have any suffix that you find with uidin, U-I-D-I-N,
then you should be thinking direct acting thrombin inhibitor.
I am being dramatic there because I want you to know
that uidin is going to be a direct acting thrombin inhibitor.
In addition, also make sure that you know about an oral anticoagulant known as dabigatran.
That would be the only one that is a direct acting thrombin inhibitor that you take orally.
Here is another one, Argatroban, but it’s dabigatran that could be given orally.
Now the problem is this.
These are newer drugs, the dabigatran would be especially,
and you may be in a state of excessive anticoagulation, and when that happens,
there is an antidote that you must know.
It’s called idarucizumab. I want you to keep that in mind please.
I also told you that with these direct acting thrombin inhibitors,
it could be an alternative to heparin
if the patient was to then develop heparin-induced thrombocytopenia.
Keep that in mind.
Let’s go and talk about that warfarin.
Now why would you’ve been considered giving warfarin?
Well, let’s say that here once again we have a patient that is in a state of thrombi formation.
Maybe it’s a DVT and obviously we can’t keep the patient on heparin forever, not a good thing,
and so therefore we need to release the patient from the hospital
and when they go home, they can now then take Coumadin or warfarin orally.
Now, it’s one situation right at home.
Or you have a patient who’s elderly and has heart disease,
maybe he has some kind of angina,
it’s stable or maybe even perhaps acute coronary syndrome.
If that’s to take place then obviously here you want to make sure
that there’s every possibility that you take a look at the ECG in such a patient.
You find not only that the heart rate here might be 150 beats per minute,
you’re trying to look for a sinus rhythm.
In other words, you’re trying to look for that P wave, and it’s not there.
In other words, it’s fibrillated.
Now obviously, I’m bringing to your attention atrial fibrillation.
Well, now that you’ve created such a turbulent flow within your left atrium,
shall we say, there’s every possibility that you’ve now developed a thrombi in the left atrium.
Think about that please.
And if that thrombi ever embolizes, where are you going?
Well, we’ve talked about this earlier
but embolization most of the time would go down to the lower extremity, no doubt.
Approximately 75% of the time it would go to maybe the renal artery
or to the superior mesenteric artery.
Okay, well, that’s complicated.
But what’s devastating is that if it ever embolizes up in the carotid.
Imagine if that happened, if it embolized into the carotid,
then your patient now is developing a stroke or a cerebrovascular accident.
So therefore, warfarin has been proven, over and over again
effectively to be a prophylactic drug in a patient who has atrial fibrillation
specifically for preventing a stroke, cerebrovascular accident.
Now, there are a couple of alternatives as well that I’ll give you in a second
but before that, let’s talk about the mechanism.
Now here, I need you to pay attention.
Warfarin works on your vitamin K dependent factors.
In other words, it inhibits the synthesis of new vitamin K dependent factors coming from the liver.
Why am I emphasizing synthesis?
Because it doesn’t neutralize the vitamin K dependent factors that are in circulation.
It does not neutralize the vitamin K dependent factors that are in circulation.
So what does that mean? Give me a second.
Warfarin works by inhibiting the gamma carboxylation or disrupting gamma carboxylation.
It does so by then inhibiting an enzyme called epoxide reductase.
Now what could happen is the following.
Now here, molecularly, here is some recent information that you wanna know.
You can have possible polymorphism in that enzyme
called vitamin K dependent epoxide reductase complex 1,
in other words, vitamin K, VK; O, epoxide reductase complex 1
and that’s the actual molecular protein.
If you have polymorphism in that enzyme,
then maybe perhaps the warfarin may or may not be as effective in that particular patient.
Is that clear?
Once you’ve understood that, then where does warfarin work?
or these vitamin K dependent factors, how many times have we discussed these?
My goodness, there’s six of them total, correct?
And I’ve told you over and over again to keep four of them separate from the other two.
II, VII, IX and X are prothrombotic, and the C and S you wanna keep separate
because those are anticoagulants.
Let’s talk about the protein C and S.
Protein C and S are anticoagulants.
It particularly works on immobilizing or in other words, it cleaves your factor V.
That is how that works.
I want you to focus on factor V.
I’ll tell you why in a little bit but protein C and S are anticoagulants
and half-life of them are very, very short.
You put all these together and here is my issue.
So here’s warfarin.
Take a look at the first sentence.
It says inhibition or disrupting normal synthesis.
What if in this particular patient the protein C and S is either deficient
or the half-life is so short, it’s completely, completely depleted.
Oh my goodness.
What do you have left in circulation?
There you go, the prothrombotic agents, right, which are II, VII, IX and X.
And the theory is that you may then develop microemboli up and down the body.
If that’s the case, then tell me where the necrosis would be.
You have widespread warfarin-induced skin necrosis.
That’s an issue.
There’s a mnemonic that I gave you earlier called WEPT.
W, warfarin; E, take a look at the E, stands for extrinsic pathway;
and P-T is the test that you’re going to measure.
Now, we’ve had this discussion as well in which II, I get it,
thrombin is the convergent point, right, of both intrinsic and extrinsic would,
through factor X, activate protrombin, no doubt.
VII is part of extrinsic, okay that makes sense.
Then IX really is part of intrinsic, so why is it that PTT isn’t elevated?
Now please know, clinically, what’s significant,
you’re only going to follow is going to be warfarin and PT and INR
and that half-life is much, much, much longer.
Not only that, but in terms of, it’s toxicity.
You’re worried about the warfarin waging war upon the fetus.
So you wanna remove the warfarin in a pregnant lady, obviously.
Now, clinical uses, we’ve talked about already, with anticoagulation,
and so therefore, we also said that it’s an oral agent.
You follow the PT and INR.
You’re thinking about prophylaxis with a stroke in a patient that has atrial fibrillation.
And with warfarin though, there are a couple of things here,
is the fact that it may then bring about skin necrosis.
So I told you that there might be alternatives.
This is true.
So up until now, we’ve talked about dabigatran a few times, a direct acting thrombin inhibitor.
But what about one in which it may inhibit directly factor X?
What’s the letter, what in Roman numeral for factor X, X. X, X
and I told you earlier that for the most part,
if you find an X in your drug such as apixaban or rivaroxaban or fondaparinux
then that would be a drug that inhibits factor X as a possible alternative to warfarin
with dealing with prophylaxis of a stroke in a patient with atrial fibrillation.