Vitamin K epoxide reductase
- Enzyme that recycles vitamin K1 (phytonadione) so that it can be used for the gamma-carboxylation and activation of clotting factors.
- Warfarin inhibits this enzyme.
- In other words, warfarin inhibits the recycling of vitamin K1 to its active form.
- Warfarin is often erroneously described as a “vitamin K antagonist.” In reality, warfarin doesn’t bind to and inhibit vitamin K directly, so this description is not accurate. Warfarin merely prevents the recycling of vitamin K to its active form, thereby antagonizing its effects indirectly.
Gamma-glutamyl carboxylase
- Vitamin K1 is a cofactor for γ-glutamyl carboxylase.
- This is the enzyme that γ-carboxylates and activates clotting factors II, VII, IX and X, as well as anti-clotting proteins C & S.
- It γ-carboxylates glutamic acid residues on these factors.
- Vitamin K does not enable the hepatic synthesis of these factors; it merely activates them.
| If you are asked which enzyme has ↓ activity in vitamin K deficiency, the answer is γ-glutamyl carboxylase.
If you are asked which enzyme has ↓ activity with warfarin use, the answer is vitamin K epoxide reductase. |
Why prothrombin time (PT) is used to monitor warfarin’s effects on vitamin K
- Warfarin is monitored with PT because Factor VII has the shortest half-life (4-7 hours) of the clotting factors, so PT will prolong before aPTT does.
- This means warfarin will prolong the extrinsic pathway (monitored with PT) before it prolongs the intrinsic pathway (monitored with aPTT).
- So if we want to accurately ascertain the effect or dose of warfarin in a patient, we need to look at the extrinsic pathway via PT because it will tell us first this information.
Vitamin K deficiency AND warfarin = ↑ PT and ↑ aPTT
- This is exceedingly HY.
- Because PT is used to monitor warfarin, people often assume warfarin ↑ PT and that’s it. But warfarin also ↑ aPTT.
- Vitamin K deficiency is most often seen in newborns because of their sterile bowels. However it can also be due to chronic antibiotic use causing disruption of colonic normal flora.
| Factor VII = extrinsic pathway only (PT)
Factor IX = intrinsic pathway only (aPTT) Factors II, X = common pathway (PT and aPTT) → This explains why vitamin K deficiency and warfarin prolong both PT and aPTT. Protein C inactivates Va and VIIIa (active forms) to V and VIII (inactive forms). Protein S is a cofactor for Protein C. |
International normalized ratio (INR)
- INR tells us how long our PT is compared to the expected range in the normal population.
- PT is normally 10-15 seconds. This means if an individual’s PT is, e.g., 14 seconds, his or her INR is 1.0.
- We aim for a therapeutic effect of warfarin on the order of INR 2-3.
- So a patient on warfarin would be expected to have a PT of 20-45 seconds in theory.
Warfarin is broken down predominantly by CYP-2C9
- This factoid is so HY it needs its own heading.
- We normally hear about CYP-3A4 in passing. Most drugs are metabolized by this CYP. But warfarin is -2C9.
| The USMLE is known to literally ask for which CYP is used for drug metabolism.
Most drugs are CYP-3A4. Warfarin is CYP-2C9. The microsomal ethanol oxidizing system (MEOS) is CYP-2E1. |
P-450 inhibitors can cause bleeding diathesis
- Ciprofloxacin (a fluoroquinoline), macrolides, sulfa drugs, and metronidazole are particularly known to cause bleeding diathesis in patients on warfarin.
Skin necrosis is an adverse effect of warfarin in those who have hereditary Protein C deficiency
- If you get a question on why a patient may have experienced warfarin-induced skin necrosis, the answer is Protein C deficiency.
- The anti-clotting Protein C has a short half-life of 8 hours, meaning it will deplete with warfarin use long before II, IX, and X do.
- This means warfarin causes a transient hypercoagulable state (which is why it must be first bridged with heparin).
- Patients who are deficient in Protein C are therefore even more hypercoagulable, leading to greater risk of clotting in cutaneous microvasculature.
Treatment for vitamin K deficiency + the reversal of warfarin
- If the need to reverse warfarin occurs, if the scenario is not emergent (i.e., there is NO active bleeding or the patient doesn’t require emergency surgery), vitamin K is merely given.
- If there IS active bleeding or the patient requires emergency surgery, the answer is fresh frozen plasma (FFP) first, THEN vitamin K.
- This is because vitamin K-mediated activation of clotting factors takes hours to days, whereas FFP works immediately, so giving vitamin K in emergency situations is futile to quickly reverse warfarin.
USMLE wants you to know vitamin K deficiency can occur in patients who are on chronic broad-spectrum antibiotics. They’ll say patient on Abx is requiring a lower dose of warfarin to achieve same INR target range – why? → decrease in colonic normal flora.
Sources of vitamin K
- Exogenously through cruciferous vegetables (i.e., broccoli, Brussels sprouts, cabbage, cauliflower, kale, etc.).
- Endogenously through synthesis by gut flora.
- On the USMLE, if they ever ask you where we get most of our vitamin K from, the answer is always via synthesis by colonic normal flora.
- That is, if “green, leafy vegetables” and “colonic normal flora” are both answer choices, the latter is always correct.
- “Green, leafy vegetables,” in contrast, is always the answer for folate.
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