Reversing Anti-coagulation: Part 1 – Warfarin (Coumadin)

Recognition of anticoagulant use in the setting of intracranial hemorrhage, GI bleed, etc is important to note as it is associated with increased morbidity and mortality. We initiate immediate medical therapy to reverse anticoagulant effects in hopes of decreasing the severity of hemorrhage or promote hemostasis.

First, some DOGMA and DOGMA-LYSIS:

• Classic teaching (aka DOGMA): "This patient has a mechanical valve, so we should not reverse their coagulopathy due to the high risk of thromboembolism and valve thrombosis."
• DOGMA-LYSIS:
  • "The incidence of mechanical valve embolism resulting in death, stroke, or peripheral ischaemia requiring surgery is 4% per patient-year (95% CI 2.9-5.2%)" (http://www.ncbi.nlm.nih.gov/pubmed/10945818)
  • Divided by 365 days in a year, this is about a risk of 0.015% per day when a patient with a mechanical valve is not anticoagulated (1 in >6000 patients) or 0.2% over 2 weeks time (1 in 500 patients). So if you think the risk of morbidity from bleeding in the setting of remaining anti-coagulated is >0.2% (which it very likely is if they're in the Emergency Department, you should probably reverse the coagulopathy).

Reversing anticoagulation: Part 1:   Warfarin (Coumadin)

• Most commonly used anticoagulant. In 2007, more than 4 million people in the US are on it.
• Reversal is accomplished by replacing the vitamin K dependent factors blocked by Warfarin (II, VII, IX, and X).
• You can reverse Warfarin acutely by giving either FFP (which contains all these factors and more) or by Prothrombin Complex Concentrate (PCC).
  • PCC is synthetically derived factors (so you don't need to worry about cross-matching blood type) that are blocked by Warfarin. There are many subtle differences amongst the many types of PCC that different drug companies develop. However, at Mayo we use Bebulin (contains II, IX, X, and additionally a small amounts of Factor VII and heparin).
  • Again, FFP and PCC are for acute reversal (we're talking minutes - hours).
  • You must also give vitamin K to maintain the reversal of Warfarin. However, vitamin K takes several hours to work (up to 12-24 hours to take full effect) as it allows new factors to be made by the liver --- that's why they're called vitamin K dependent factors.
• The main advantage of Bebulin compared to FFP is that much smaller volumes of administration are needed.
  • Bebulin is around 100cc. People consistently underdose FFP. You need approximately 15cc/kg to start, which for a 70kg patient, is going to be around 4 units of FFP. 2 units is not enough. Sometimes, even as many as 10 units of FFP may be necessary.
  • Keep in mind, that FFP, unlike 0.9% NS, will essentially all stay in the intravascular space. So giving 4 units of FFP is the equivalent intravascular volume of giving at least 3L of 0.9% NS to a patient. You can see that FFP can run into problems with fluid-overload especially in a patient with CHF.
  • Additionally, being reconstituted (meaning you stir the Bebulin magic-powder into a solution and you're ready to give it via IV), it can be administered more quickly as it does not need to be thawed (why it’s called fresh FROZEN plasma).
• PCC has been shown to reverse INR faster than FFP (this makes sense... because it takes forever to thaw and give 4-10 units of FFP). It has been also been shown to decrease the rate and final size of hematoma expansion in an intracranial hemorrhage compared to FFP.
  • However, PCC has never been shown to improve any single patient-oriented outcome compared to FFP (a patient-oriented outcome is what matters: mortality or morbidity/neurologic function). That said, we hope that PCCs can help patients and we know that it can reverse INR faster in life-threatening situations.
• Lastly, remember that PCC is concentrated clotting factors. So you can imagine that it would carry some risk of doing more than just reverse anti-coagulation, but actually cause a clot. The incidence of thromboembolic events with 3 factor PCC is around 0.7%. (Slightly higher ofr 4 factor PCC) http://www.ncbi.nlm.nih.gov/pubmed/21800002

Summary of Warfarin associated bleeding:

• In any serious bleeding on Warfarin, you should consider PCC or FFP for acute reversal. And Vitamin K 5-10mg IV for long term reversal. PCCs are dosed based on INR and patient weight. Ask pharmacy for help. While PCCs have never been found to help patients compared to FFP, the standard of care these days in serious life-threatening bleeding (including any intracranial bleed) is to give PCC if readily available.

In a future shift pearl, we’ll discuss reversal of Dabigatran (Pradaxa), the Xa inhibitors - Rivaroxaban (Xarelto) and Apixaban (Eliquis), heparin and more!