Once upon a time, in a land not too far away, there were two residents and an attending discussing various cases in the ED. The day had started off slow and typically that meant it was "scenario time."
Dr. Quillet loved to play a game called "Reversal Rehearsal." The game involved a deck of cards. Each card had a patient presentation, some form of anticoagulant, and asked: "If, why, and how the agent should be reversed." He thought this game was brilliant and ALWAYS carried these cards around in his white coat.
Maria reached for the card and flipped it over.
This patient was named Betty Crocker, and unfortunately, on her way to a doctor's appointment, she was tossed from the wheelchair onto the floor of the van. The wheelchair van operator had not secured her properly, and an ambulance was needed due to Mrs. Crocker's injuries.
Betty was hypertensive, confused, and on a medication called warfarin. Betty's daughter explained that her mom had been prescribed warfarin because of her atrial fibrillation. The erratic fibrillation of the atriums can allow blood to not fully be ejected. For this reason, patients with atrial fibrillation are at risk for blood clots/strokes.
Due to Betty being on a medication that causes her blood to not clot as easily, she routinely has to get a specific lab value checked called an INR (International Normalized Ratio).
Maria, without hesitation, explained that an INR is really just a comparison of the patient's prothrombin time compared with a normal prothrombin time (PT).
A prothrombin time is a look at the external pathway of the coagulation cascade. Interestingly enough, the reason it is called the "external" pathway is due to the way the laboratory test is done (I will explain in just a second). When the blood is collected from the patient, it is put in a tube that contains sodium citrate. The citrate will bind to the calcium in the collected blood and prevent it from clotting. When it arrives at the lab, the clinical lab scientist or technician will need to separate the blood cells by a method called "centrifugation." Once the plasma component is isolated, two additional things will need to be added in order to begin the test.
It makes sense that we would need to add calcium in order to start the clotting. Technically this does not really count as an "external" additive, because it naturally exists in the blood. However, the reason the "external" pathway got that name, is because of how it clots in the tube, not the body. In order to kick off the external pathway, a substance that does not normally exist in the blood, called tissue factor, will need to be added. Tissue factor can normally be found in closed up tiny particles within the subendothelium or inflammatory cells.
The normal prothrombin time is typically around 10-13 seconds. However, this "normal" can vary based on the lab and the re-agents being used, this is why the INR is helpful. The INR compares the patient's PT with the normal PT for that lab.
In the example above you can see that if we divide the patient's PT with the control (normal) PT, we get an INR of 1. If the patient's PT was 24 seconds, our INR would be 2.
When we look back at Betty Crocker's INR, it was 6. That is definitely higher than therapeutic and puts her at increased risk for bleeding. Let's take a look at her CT.
Maria and Kyle both agree that the Coumadin needs to be reversed, but how exactly is this done?
"The history of warfarin is actually pretty interesting," says Dr. Quillet.
Back in the 1920s, farmers in North America and Canada, noticed their previously healthy cattle were dying from internal bleeding. Their cattle would graze on sweet clover hay, and when it would get damp, the mold would deactivate something in the cows that caused them to bleed more.
Eventually, a farmer from Wisconsin had enough of this cow-dying crap and drove a dead cow 200+ miles to an agricultural experiment station. He presented the scientists with a milk can of unclotted blood. They eventually discovered that the moldy hay inhibited an enzyme called "epoxide reductase" resulting in depletion of reduced vitamin K.
You see, vitamin K is needed to mature factors II, VII, IV, and X. I imagine vitamin K as the person handing out diplomas at graduation to these factors. Once they graduate, they can go on and get a nice job in clot formation, but vitamin K antagonists, such as warfarin, prevent that ceremony from happening (the streaker).
Vitamin K is stored in two different forms within our body, active and inactive. The ability to essentially turn vitamin K off and on prevents us from bleeding to death if we don't eat leafy green vegetables on a daily basis (guilty). However, if the switch that activates vitamin K (epoxide reductase) is damaged, those little graduating factors will not get their diploma and thus will be unemployed. "
So how do we reverse it?
Reversing a vitamin K antagonist involves not only replenishing the factors that are missing (II, VII, IV, and X) but also administering vitamin K to mature the factors naturally produced in the body once the external factors have been broken down.
Replenishing factors: Prothrombin Complex Concentrate or Plasma
Maturing your own intrinsic factors: Vitamin K.
Vitamin K takes about six hours to start working (longest graduation ceremony ever). For that reason, it should be given early. In addition to the vitamin K, PCC or/and plasma should be started in the meantime, while we wait for the K to kick in. The timeline looks something like this.
Maria and Kyle are impressed with how much they remembered from last week's ground rounds on vitamin K antagonist mechanism and reversal. They both feel confident that they could have treated Betty Crocker efficiently and given her the best chance of strong recovery as possible!
Oh! By the way, why do you think her INR was so elevated? Send your responses to email@example.com for a chance to win a free FOAMfrat T-shirt!
Levi M, Eerenberg E, Kamphuisen PW, Bleeding risk and reversal strategies for old and new anticoagulants and antiplatelet agents. J Thromb Haemost2011;9:1705-12.doi:doi:10.1111/j.1538-7836.2011.04432.xpmid:21729240
Lim, G. Warfarin: from rat poison to clinical use. Nat Rev Cardiol (2017). https://doi.org/10.1038/nrcardio.2017.172
National Institute for Health and Care Excellence. Atrial fibrillation: management (clinical guideline 180). 2014. www.nice.org.uk/guidance/cg180.
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