DOAC reversal

Reversing the new oral anticoagulants.

Till recently reversing the “Xabans” and the Direct Factor II inhibitor medications has been a challenge.   Unlike Warfarin which is reversed using Vitamin K, and Heparins which are reversed using Protamine Sulphate; the new direct oral anticoagulants (DOACs) don’t have a magic antidote.

In this post, I’ll unpack the way these new drugs work, and then discuss how they will be reversed if your patient is bleeding from trauma, or requires surgery.

If you’ve seen my YouTube then you will have a good understanding on the differences between blood clotting and blood coagulating (you should start there if you thought they were the same thing).

Fast forward to the #DOAGs section if you’re all over this coag cascade stuff.

Ok

Ultimately the solidification of blood to form a thrombus requires these two separate processes- clotting and coagulation which is the conversion of a cocktail of proteins (coag factors) in blood, from liquid state to a solid stringy strandy dental floss like product that, like string on a birthday parcel holds a parcel of clotted cells (RBC & Platelets) together.

That string is called FIBRIN

Here is where we start. 

If you can’t make fibrin, you can’t coagulate.   The complex cascade of chemical reactions in your blood which forms fibrin, is called coagulation.  Any drug that stops that chain reaction is called an Anti-coagulant.

Simple steps in the common coagulation pathway involve 4 players.

Vitamin K

Factor X (remember that ‘X’) though it’s pronounced “factor 10.”

Factors 2(Factor II) also called Prothrombin

Factor 1 (Factor I) also called Fibrinogen.

Now tissue injury and chemicals released from the platelets and vessel wall cells stimulate the coagulation chain reaction- think of a finger on dominoes.  This activates Factor X.  But this go button needs calcium and vitamin K to allow the cascade to start.

So Factor X activates now called Xa.

Xa activates Factor II Prothrombin 

Which is now called IIa (or Thrombin).

IIa activates factor I

which is technically Factor Ia (aka Fibrin).

Anticoagulants.

Warfarin deactivates vitamin K so the prices can’t start

Heparins/enoxaparin directly prevents the activation of FX into Xa and also stops Prothrombin (Factor II) activating into thrombin Factor IIa.

Now #DOACs 

Direct Oral AntiCoagulants inhibit one of two pathways.

The Xabans- (apixaban, rivaroxaban, edoxaban)

Their name with an “Xa” in indicates that they Ban the Xa-   They actually deactivate factor Xa.   

Remember once activated FX turns to FXa which converts Prothrombin FII.

The Xabans stop (ban) coagulation at that Xa step. 

Dabagatran (Pradaxa) is different.  It waits till Thrombin (IIa) forms then deactivates it so it can’t convert fibrinogen into strings of fibrin.

Now stopping these drugs is not possible, so to help the patient coagulate, we need to stimulate the Fibrinogen directly, or, in the case of Pradaxa, stimulates Prothrombin earlier in the chain reaction.

Now bleeding patients:

On warfarin we can reverse it giving a large bolts of Vitamin K.

Heparin is reversed using protamine.

DOACs are short acting (5-17 hour half lives) , so unless someone just took their dose today, reversal and severe bleeding is rare, making these anticoagulants quite safe.   But what if we don’t have that 5 hours?? 

If available, idarucizumab is recommended for reversal of anticoagulant effects for patients taking Dabigatran.

It is an antibody that binds to the drug blocking its effects on Thrombin.

For the Xabans, the reversal is harder, 

Many have tried and failed, and perhaps the fact that these drug are so short acting that motivating some research and development isn’t seen as worthwhile or profitable.  So we are left with few options; none of which are great.

Charcoal:

If taken inside 4-6 hours of last Xaban dose, activated charcoal orally can bind with Rivaroxaban and Apixaban.

Andexanet alfa, the first agent shown to reverse the anticoagulant effects of rivaroxaban and apixaban, has been approved by the FDA, according to statement from Portola Pharmaceuticals in early May 2018.  It is a factor Xa “decoy” molecule that acts by attracting and sticking to Xabans, thereby preventing them from interacting with actual factor Xa, but andexanet also has a short half life and hence the effect quickly reduces once treatment stops, so needs a complex infusion.

Factor VII - 4factor PCC

FEIBA 50 IU/kg (contains factors 2,7,9 an 10 in predominatly inactivated form as wellas activated factor 7 and 1-6 units of Factor VIII coagulant antigen (FVIII C:Ag) per mL)

Prothrombin-X

Current guidelines do not recommend use of prothrombin complex (Prothrombinex-VF in Australia) but it has been shown to normalise prothrombin time in a trial of 12 healthy male subjects at a dose of 50 IU/kg iv infusion (Eerenberg et al., 2011).

Tranexamic acid (TXA)

Not new, and scraping the bottom of the barrel, but TXA has been used in severe bleeding since Moses hunted Brontosaurus.   It is only used in bleeding patients with Xabans or Dabigatran, if bleeding is severe- ie trauma. Classified as a Plasminogen inhibitor, it really only helps you to maintain any coagulation you’ve been able to make already. So given that DOACs inhibit/slow down coagulation and don’t stop it completely, preserving any thrombus you’ve formed is what you want when you’re bleeding.  TXA does this by preventing body enzymes (plasminogen) dissolving the clots you already made.

Platelets , FFP and RBC 

Again, only if bleeding.   It stands to reason that as you bleed you also loose the DOAC drugs . So transfusions of unadulterated blood products acts to correct not only losses, but dilute the plasma bound DOACs.

Well that’s about it, so Q&A is open.

#RobTimmings #ECT4Health

This content is available in our #RustyPills pharmacology course, and #CardiacSeminars.
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