Blood & Clots Series: When and how should I reverse anticoagulation with warfarin?

In Blood & Clots, Medical Concepts by Matthew NicholsonLeave a Comment

All the content from the Blood & Clots series can be found here.

CanMEDS Roles addressed: Medical Expert

Case Description

You are in the emergency department seeing an 89-year-old female presenting with five episodes of coffee ground emesis over the last twenty-four hours. She has atrial fibrillation and is on long-term warfarin for stroke prevention. She also has CAD and had two drug eluting stents placed 4 years ago but is no longer on dual antiplatelet therapy. Her hemoglobin has dropped from her baseline at 140 to 95 and her INR is 3.8.

Main Text

Background

Determining the need for warfarin reversal can be challenging, but in cases of major bleeding reversal is clearly indicated. Patients have an elevated risk for bleeding when INR values go above the target of 2.0-3.0. Any patient with major bleeding, intracranial hemorrhage, or a need for urgent surgery should receive targeted reversal agents to reduce bleeding.  In extensive life-threatening exsanguination, massive transfusion protocols may also be relevant but this has been discussed in a previous article.

Vitamin K antagonists inhibit vitamin K-dependent synthesis of coagulation factors II, VII, IX and X and of the endogenous anticoagulation factors proteins C and S. The urgent reversal of warfarin should always include:

  1. Immediate replacement of clotting factors with prothrombin complex concentrates (PCC)
  2. Concurrent administration of intravenous Vitamin K to ensure ongoing hemostasis after the effects of PCCs wear off (usually after six hours)

Prothrombin Complex Concentrates (PCCs)

Prothrombin complex concentrates (PCCs) contain all of the factors (II, VII, IX, X, and proteins C and S) that depend on vitamin K and are affected by warfarin, making PCCs the ideal products for reversing the effects of warfarin. The three and four-factor versions are considered therapeutically equivalent. Note that PCCs contain a small amount of heparin to prevent the solution from clotting on the shelf and should never be given to patients with an “allergy” to heparin (ie. history of heparin-induced thrombocytopenia (HIT)). The risks of PCC administration will be discussed in the next Blood and Clots post.

Prothrombin complex concentrates are either dosed based on INR alone or dosed based on weight and INR. It’s important to follow local hospital guidelines for dosing. If the INR is unknown and PCCs need to be administered before results are ready, most recommend an empiric dose of 2000 IU.  The maximum recommended dose is 3000 IU for a single dose. Examples of dosing can be found here.

INR can be re-checked 20-30 minutes after administration of PCC to ensure adequate dosing to achieve an INR <1.5. If the INR remains above 1.5, additional doses of PCC can be given.

Co-administration of Vitamin K

Administration of intravenous vitamin K is the true “antidote” to warfarin. Its only  drawback is its time to take effect. Vitamin K 10mg by intravenous infusion starts to work within 6-12 hours and reaches full effect occurs within 24 hours compared to oral dosing, which acts in about 18-24 hours.

Frozen Plasma should not be used to reverse warfarin

The only situation where frozen plasma (FP) should be used for warfarin reversal is in patients who cannot receive PCCs (ie previous episode of HIT) or if PCCs are not available.  While FP contains the necessary factors to reverse warfarin anticoagulation, it has several disadvantages compared to PCCs.

  • Most importantly, PCCs have been demonstrated to have a mortality benefit compared to FP when reversing warfarin for patients who have major bleeding or require urgent surgery 1.
  • PCCs can be prepared and administered faster than FP, which requires up to 40 minutes for thawing and ABO typing.
  • FP can take up to 2-4 hours to administer given the larger volume (approximately 1L compared to 80mL/2000IU of PCC) and put the patient at risk of fluid overload.
  • FP also does not have any viral inactivation, though the risk of viral transmission through modern blood products is extremely low.

Notably, FP should also be co-administered with vitamin K if it is used.

While PCCs are available at the vast majority of centers in Canada (even smaller and remote sites), if your site’s blood bank does not stock PCCs we recommend advocating for them to be made available. From a blood bank perspective, PCCs are easier to stock as they do not require freezer space (they are stored as a lyophilized powder), they do not require a plasma thawer, and they have a longer shelf life than FP.

Restarting anticoagulation?

A recent meta-analysis demonstrated that resuming warfarin after interruption for gastrointestinal bleeding is associated with a reduction in thromboembolic events and mortality compared to not resuming warfarin, where the risk of recurrent GI bleeding is not statistically higher.  Similar findings were seen in a meta-analysis for resuming warfarin after interruption for intracranial hemorrhage. The 2018 American Society of Hematology guidelines has a weak recommendation that patients receiving anticoagulant for venous thromboembolism should restart anticoagulation after two weeks, but not more than 90 days. The optimal timing of resuming anticoagulation is an area that needs further study 2.

Case Conclusion

You treat the patient with 2000 IU of PCCs and 10 mg of vitamin K given IV after obtaining consent from the patient.  The patient’s INR goes down to 1.1 and the patient is seen by gastroenterology. They perform endoscopy and are able to treat the lesion.  The patient requires two units of RBCs as their hemoglobin dropped below 70 g/L. They have a complicated course in hospital, but are discharged home on anticoagulation therapy.

Main Messages

  • In major bleeding or urgent major procedures patients anticoagulated on warfarin the standard of care is co-administration of vitamin K (10 mg IV) and PCCs
  • PCCs are typically dosed based by INR +/- weight.  An empiric dose if the INR is not known is typically 2000 IU.
  • Frozen plasma is inappropriate for warfarin reversal unless PCCs are unavailable (which should generally not be the case) or the patient has had a previous reaction to heparin (PCCs contain heparin)

 

Additional Readings

All the content from the Blood & Clots series can be found here.

This post was reviewed by Brent Thoma, Anali Maneshi and uploaded by Rebecca Dang.

References

1.
Chai-Adisaksopha C, Hillis C, Siegal D, et al. Prothrombin complex concentrates versus fresh frozen plasma for warfarin reversal. A systematic review and meta-analysis. Thromb Haemost. 2016;116(5):879-890. [PubMed]
2.
Witt D, Nieuwlaat R, Clark N, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: optimal management of anticoagulation therapy. Blood Adv. 2018;2(22):3257-3291. [PubMed]
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Matthew Nicholson

Matthew Nicholson

Matthew Nicholson is pursuing his hematology fellowship at the University of British Columbia. He's passionate about medical education, cycling, music, and he has been known to get lost in a good book.
Matthew Nicholson
- 2 days ago
Andrew Shih

Andrew Shih

Dr. Andrew Shih works as a Transfusion Medicine specialist at Vancouver Coastal Health Authority. His interests include education regarding the safety and appropriate utilization of blood products and advance blood transfusion as a personalized medical therapeutic intervention.