Anticoagulants: Warfarin

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Introduction0:00–0:33

Anticoagulant medications are used to prevent blood clots from forming. These medications work by interfering with the normal function of plasma proteins called coagulation factors, which take part in secondary hemostasis.
But let’s focus specifically on the anticoagulant warfarin, which works by preventing the synthesis of coagulation factors II, VII, IX and X, and anticoagulation proteins C and S.
Now, to understand the regulation of clot formation we first need to talk briefly about hemostasis-- in which hemo refers to the blood, and stasis means to halt or stop.

Pathophysiology0:33–4:45

Hemostasis is divided into two phases: primary and secondary hemostasis. Primary hemostasis involves the formation of a platelet plug around the site of an injured blood vessel, and secondary hemostasis reinforces the platelet plug with the creation of a protein mesh called fibrin.
To get to fibrin, a set of coagulation factors each of which or enzymes need to be activated. These enzymes are activated via a process called proteolysis- which is where a portion of the protein is clipped off.
In total, there are twelve coagulation factors numbered factors I-XII, but there’s no factor VI. Most of these factors are produced by liver cells, and it turns out that producing coagulation factors II, VII, IX, and X requires an enzyme that uses vitamin K.
Now, when vitamin K is absorbed from the digestive tract and travels to the liver, it’s in its dietary form and it’s called vitamin K quinone.
An enzyme, called quinone reductase, takes electrons from NADPH, and donates them to vitamin K quinone, converting it into the reduced form which is called vitamin K hydroquinone.
Then, vitamin K hydroquinone acts as a cofactor by donating its electrons to an enzyme called gamma glutamyl carboxylase, which converts the non-functional forms of coagulation factors II, VII, IX, and X into their functional forms.
Gamma glutamyl carboxylase adds a carboxyl group, which is a chemical group made up of one carbon, and two oxygens, onto the end of glutamic acid residues on the proteins.After the carboxylation step, vitamin K is in an oxidized form, where it can accept electrons, and it’s called vitamin K epoxide.
Vitamin K epoxide gets converted back into vitamin K quinone by another enzyme called vitamin K epoxide reductase, or VKOR, which donates electrons to vitamin K epoxide using a thiol group.
In this fashion, a single molecule of vitamin K can be reused many times. As it turns out, the drug warfarin, which was first used as a rat poison, blocks the function of this enzyme which blocks vitamin K from getting recycled and as a result factors II, VII, IX, and X don’t get activated.
Now let's take a closer look at the coagulation cascade to see where these coagulation factors play their respective roles.
The coagulation cascade begins via two pathways --the extrinsic and intrinsic pathways. The intrinsic pathway starts when circulating factor XII comes into contact with the surface of activated platelets or collagen.
Activated factor XII, then activates factor XI, which activates factor IX which activates factor X. Factor X starts the common pathway where it activates factor II, which activates factor I that builds the fibrin mesh.
When factor II gets activated it also activates 4 other factors: V, VIII, IX, and XIII. Factor V gets activated and acts as a cofactor for X, factor VIII acts as a cofactor for factor IX, and factor XIII helps factor I, or fibrin, form crosslinks.
In the extrinsic pathway, exposed tissue factors on the damaged blood vessel activates factor VII, which activates factor X and starts the common pathway.
So without vitamin K, the loss of factor VII means that the extrinsic pathway won’t function; the same goes for factor IX; and without factor X and II, the common pathway won’t function.
Warfarin is taken per-oral and it affects the extrinsic pathway first since factor VII has the shortest half life and it’s the first coagulation factor to run out.

Mechanism of Action4:45–6:48

Next, levels of factor II, IX, and X also drop, causing inhibition of the intrinsic and common pathways. Since factor VII drops first, warfarin’s efficacy is monitored using a blood test called prothrombin time, or PT, which is a measure of how well the extrinsic and common pathways are functioning.
To perform this test, blood is drawn and the plasma is separated out by centrifuge. The plasma contains all the coagulation factors minus tissue factor, which is normally found within the blood vessel walls.
Next, tissue factor is added to the plasma to trigger coagulation, and the time until the sample clots is measured. This measurement is called the prothrombin time, also abbreviated as PT and it’s compared to the control PT, which is the time it takes for the blood to clot in a healthy person.
Now the problem with PT is that there are multiple testing kits from different companies and they all cause clotting at different rates.
So it’s helpful to convert the PT into a standardized value called the INR, or international normalized ratio. This can be done by dividing our patient’s PT by the control PT provided by the company.
For example, if the person’s PT is 22 seconds and the control PT is 11 seconds, their INR is 22/11 or 2. This means that that person’s blood takes twice as long to clot compared to a healthy person.
A normal INR is 1.1 or less, but for someone taking warfarin, the usual goal is an INR between 2 and 3. The main use for warfarin is in the prevention of disorders caused by blood clots.

Indications6:48–7:44

These include deep vein thrombosis, or DVTs, which is when venous blood clots called thrombi form in the deep veins of the legs.
These thrombi can cause pulmonary embolism when they travel to the lungs and block off arteries. In people with arrythmias, particularly atrial fibrillation, the blood could pool in the heart, leading to blood clot formation.
These clots then get pumped out of the heart, and make their way to the brain where they block off cerebral arteries and cause strokes.
Other common causes of blood clot formation in the heart include prosthetic heart valves and recent myocardial infarctions.
Warfarin is the medication of choice for preventing these problems because it’s taken peroral, so it’s very convenient. In terms of toxicity, the most common problem with warfarin is uncontrollable bleeding, most commonly in the GI tract.

Toxicity7:44–11:27

Bleeding can occur even at therapeutic levels, but the risk increases when INR is higher than 3. This can result when the dosage is too high, when other medications prevent warfarin from being metabolized, or when there is a polymorphism in the gene for VKOR leading to reduced function of the enzyme.
Normally, warfarin is broken down in the liver by an enzyme called CYP2C9 which belongs to a class of enzymes called CYP450 oxidase.
Certain common medications like cimetidine, omeprazole, metronidazole, trimethoprim/sulfamethoxazole, and amiodarone can inhibit this enzyme and cause warfarin to accumulate, thus increasing the INR.
On the other hand, some medications like griseofulvin, barbiturates, phenytoin and carbamazepine can enhance the activity of CYP450 which speeds up the metabolism of warfarin and we get an subtherapeutic INR that’s under 2.
Therefore it’s extremely important to find out what medications the person is taking before initiating warfarin therapy.
Next, warfarin is contraindicated in pregnancy due to its teratogenic effects. It increases the risk of fetal hemorrhage, spontaneous abortion, bone deformities and ophthalmologic abnormalities, such as optic neuritis.
Another problem is warfarin induced skin necrosis which is caused by tiny thrombi forming in the blood vessels in the skin.
This happens because warfarin also inhibits the synthesis of the functional form of a vitamin K-dependent anti-coagulation protein called protein C.
Normally protein C combines with protein S to form a proteolytic complex which inactivates factor Va and factor VIIIa. Now, protein C has an even lower half life than factor VII, so they are the first to disappear when someone takes warfarin, and hypercoagulation happens before the anticoagulation.
Patients with congenital protein C deficiency, meaning they have lower levels of protein C to start with, have an increased risk of warfarin induced skin necrosis.
So, to combat this, another anticoagulant called heparin is often given at the start of warfarin therapy. Heparin enhances the activity of another anticoagulation protein found in the body called antithrombin III, which normally inactivates activated factor II (or thrombin) and factor Xa.
This balances things out until the anticoagulative effects of warfarin kick in and it’s referred to as “heparin bridge”.If a person suffers a severe warfarin overdose, meaning they have an INR higher than 10, warfarin should be stopped and vitamin K.
Vitamin K promotes the synthesis of new clotting factors and therefore, reversal of warfarin is slow. Now, if there’s active bleeding, rapid reversal of warfarin is needed.
So, warfarin should be stopped and the patient should be given fresh frozen plasma, or FFP, since it contains all clotting factors, or prothrombin complex concentrate, also known as PCC, which contains the coagulation factors II, VII, IX and X along with proteins C and S.

Review11:27–11:56

All right, as a quick recap, warfarin is an anticoagulant that works by inhibiting vitamin k epoxide reductase for factors II, VII, IX, X, protein C and protein S.
It is administered orally as a long-term anticoagulation strategy to prevent clot formation. Its toxicity profile includes bleeding, medication interactions, teratogenicity, and skin necrosis due to the initial,
Anticoagulants: Warfarin: Video, Uses, Mechanism | Osmosis