As recently as 2010, warfarin was the only oral anticoagulant available. It was and continues to be a ground breaking drug but there is a lot to consider to minimize the risks associated with its use.
There is alot of necessary information in this study unit. My goal, as always, is to present it in a logical sequence that builds from foundational elements to the complexities of clinical application.
Mechanism of Action
The mechanism of action of warfarin is summarized in the name of its drug class: vitamin K antagonist.
Warfarin prevents the activation of vitamin K in the body by inhibiting the enzyme “vitamin K epoxide reductase complex 1 (VKORC1)”. This is the enzyme responsible for the conversion of inactive vitamin K to active vitamin K.
Without active vitamin K the liver cannot produce clotting factors: II, XII, IX, X.
Protein C and protein S are natural anticoagulants that also require vitamin K for activation.
It is this inhibition of the clotting factors that leads to the anticoagulant effects of warfarin.
Warfarin has a very narrow therapeutic index. Clinical efficacy of warfarin is gauged by monitoring the International Normalized Ratio (INR). In most cases the INR goal range is 2-3 for patients on warfarin. The INR value is essentially an estimate of how long it takes your blood to clot.
There are many factors that can affect INR including drug interactions, acute illness and food. Because of this warfarin requires regular assessment of INR.
We will consider each of these factors below because they are truly the things we see in practice that have a significant impact on patient outcomes.
Drug Interactions
Drug interactions with warfarin fall into 4 broad categories based on the mechanism of the interactions:
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1. Altered Warfarin Metabolism
The most significant drug interactions concerning warfarin are related to the cytochrome P 450 (CYP) enzymes and P-glycoprotein (P-gp) transporters.
CYP enzymes are responsible for the metabolism of over 70% of drugs in clinical use. P-gp transporters and CYP enzymes share many substrates. Because of this they are often considered together as CYP/P-gp interactions.
If you are unsure about how CYP enzymes and PGP transporters work in the body, I strongly recommend that you review the Cytochrome P450 and P Glycoproteins study unit. CYP/P-gp interactions are prevalent throughout pharmacology and very clinically significant. It is worth truly understanding these interactions because you will see them often in your career.
With regards to warfarin, CYP/P-gp interactions are highly significant. The most relevant are 3A4, 2C9 and 2C19. CYP/P-gp inhibitors will increase the amount of warfarin in the body and therefore increase the risk of bleeding.
CYP/P-gp inducers will decrease the amount of warfarin in the body which can increase the risk of thrombosis in AF. The Cytochrome P450 and P Glycoproteins unit has videos that will help you truly understand how induction and inhibition of these enzymes alter drug concentrations.
With all this acknowledged, it is important to know that warfarin will be your preferred oral anticoagulant in a patient who must also be on a strong CYP/P-gp inducer or inhibitor.
This is because, if we know and anticipate those interactions we can compensate by adjusting the dosing of warfarin based on INR. This is one significant advantage of warfarin not having a standard dosing regimen, it can be adjusted on an individual patient basis.
2. Altered Vitamin K Levels
From our earlier discussion of the mechanism of action of warfarin, we know that the presence of active vitamin K is necessary for the formation of clotting factors II, VII, IX and X.
Anything that affects the levels of vitamin K in the body will have an effect on the level of baseline coagulation. For a patient on warfarin, changes to the baseline coagulation can easily nudge them out of the narrow therapeutic range of 2-3.
We get vitamin K from 2 sources: from food and from the body
3. Altered Platelet Function
To maintain hemostasis platelets are needed in the initial response to clot formation. This includes platelet adhesion, activation and aggregation.
Platelets are also needed in the second level of response to clot formation which is the activation of the coagulation pathway. Therefore, any drug that affects platelet function will compromise the body’s ability to respond to triggers for hemostasis.
For patients on warfarin we want to decrease the tendency of blood to clot but not prevent it completely.
If a patient is on warfarin and a drug that impairs platelet function both platelet and clotting factor function are impaired placing them at a higher risk of hemorrhage.
This increased risk of bleed from platelet affecting drugs will not be reflected in the INR.
Antidepressants (SSRIs), antiplatelet drugs (P2Y12 antagonists like clopidogrel, prasugrel), aspirin, fish oil, ginko biloba, garlic and anti inflammatory agents (naproxen, diclofenac) all affect platelet function and increase the risk of hemorrhage in patients taking warfarin.
4. Altered Warfarin Absorption
Any drug that affect warfarin absorption from the gastrointestinal tract will affect INR levels. This includes agents like cholestyramine and sucralfate. These agents tend to bind or sequester anything else in the GI tract hence preventing absorption.
Benefits of Warfarin
We’ve just discussed the major drawbacks of using warfarin: drug interactions, food interactions and a very narrow therapeutic range. But there are some significant advantages with warfarin.
Achieving and maintaining INR with warfarin is different for each patient, which makes it useful in patients who are not eligible for the standard dosing regimens of other agents. For example, warfarin has zero renal clearance therefore we can use warfarin in patients with very poor renal function by adjusting the dose based on how the patient responds after a few doses.
Warfarin is also very affordable.
Warfarin remains the first line oral anticoagulant in patients with AF and moderate-severe rheumatic mitral stenosis or mechanical heart valves per the 2023 AF Guidelines. The RE-ALIGN (dabigatran) and PROACT Xa (apixaban) trials both enrolled patients with mechanical heart valves and atrial fibrillation. Both had to be stopped early because of higher thromboembolic events with the study drugs.
Now that you have a solid foundation on how warfarin work, learn how to actually dose warfarin in practice.
If you’ve found this unit helpful, I would love to hear from you! Leave a question or comment below.
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The information on this website is intended to be used solely for educational and informational purposes. While the content may be about specific medical and health care issues, it is not a substitute for or replacement of personalized medical advice and is not intended to be used as the sole basis for making individualized medical or health-related decisions.
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