Blood & Clots Series: What are the risks of reversing anticoagulation?

In Blood & Clots, Medical Concepts by Andrew ShihLeave a Comment

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

CanMEDS Roles addressed: Medical expert, Communicator

Case Description

You are working a shift in your local emergency department and an 89-year-old female is brought in with a 2-day history of melena stool.  The patient has a history of atrial fibrillation and uncontrolled hypertension despite being on an ACE-inhibitor. Her initial bloodwork shows a hemoglobin of 102 g/L (no baseline provided), otherwise normal CBC, creatinine of 202, and an INR of 4.2.

She is with her family and since you’re considering reversing her warfarin anticoagulation with vitamin K and prothrombin complex concentrates (PCCs), you begin to discuss the risks of reversal especially as PCCs are a blood product.  What are you going to tell her and her family about the risks of thrombosis? This also gets you thinking: what other thrombotic risks exist for other therapies to reverse anticoagulation in a bleeding patient?

What are the risks of reversing anticoagulation?

One of the main risks of reversing anticoagulation in a bleeding patient is thrombosis.  Unfortunately, studies to determine efficacy are not designed to determine the level of risk from reversing anticoagulation.  It is also unclear whether the reversal agents have intrinsic risk or the risk comes from the fact the patient has an underlying disorder which may make them coagulopathic.

Prothrombin Complex Concentrates (PCCs)

Two systematic reviews assessing the thrombosis risk of PCCs for warfarin reversal demonstrated the rates was 1.4% and 2.7% respectively  1, 2.  When comparing the effectiveness of PCCs compared to plasma, a systematic review found that across three studies the thrombosis risk was 4.1% 1. This was not significantly different than frozen plasma (FP) treated patients (4.9%).  However, the use of PCCs compared to FP demonstrated a mortality benefit (OR 0.56). The lower incidence from the previous reviews is likely due to different studies selected, which may have measurement bias and shorter durations of follow up.

Vitamin K is co-administered typically with PCCs for warfarin reversal and most of the studies assessing PCC reversal of warfarin also co-administered vitamin K.

Little data exists for thrombotic risk of PCCs to reverse factor Xa inhibitors.  Two prospective cohort studies in this area found major thrombotic events in 3/84 (4%) 3 and 5/66 (8%) 4 patients respectively.

Activated Prothrombin Complex Concentrates (aPCCs)

No data currently exists on thrombosis risk for aPCCs in anticoagulant-related bleeding.  The thrombotic risk observed in hemophilia patients is 4-8 per 105 infusions 5.  However, given dabigatran can be reversed with idarucizumab, there is little role for use of aPCCs in this setting.

Recombinant Factor VIIa (rfVIIa)

There is no clear evidence supporting the use of rfVIIa in treating bleeding without hemophilia and there is a significant increase in arterial thrombotic events reported from RCTs (RR 1.45) 6.

Tranexamic Acid (TXA)

Meta-analyses of trials for TXA use in acute traumatic injury, emergency and urgent surgery, gastrointestinal bleeding, or menstrual bleeding have found an increased risk of thrombotic events7–10.  A meta-analysis of 268 RCTs demonstrated no thrombotic risk of TXA in perioperative trials compared to placebo or no intervention 11. However, patients who have a history of thromboembolism or were on anticoagulation are typically excluded from RCTs.  The totality of the evidence that exists demonstrates that risks of thrombosis are minimal and TXA should not be avoided for concerns regarding thrombosis.

Idarucizumab (antidote for dabigatran)

In the REVERSE-AD study, a multicenter prospective study of using idarucizumab to reverse the anticoagulant effects of dabigatran in uncontrolled bleeding and urgent procedures, the thrombosis rate amongst 503 patients was about 5% and 7% at 30 and 90 days after reversal 12.  The drug itself, however, does not induce thrombin generation in healthy volunteers suggesting that the thrombosis rate may be due to the underlying coagulopathy than the reversal agent 13.

Andexanet Alfa (antidote for anti-Xa inhibitors)

In the ANNEXA-4 study, a multicenter prospective study of using andexanet alfa to reverse the anticoagulant effects of anti-Xa inhibitors (apixaban, edoxaban, rivaroxaban) in patients with major bleeding there were 24 thrombotic events in 228 patients (11%) 14.  Similar to idarucizumab, the drug itself did not produce thrombotic events when studied in healthy volunteers 15. Increases of prothrombotic laboratory markers were seen, but it is unclear if these findings are clinically significant.

Other Therapies

Vitamin K likely does not have any intrinsic risk of producing thrombosis, though this is not well studied.  A meta-analysis of 21 studies only had one study that assessed for adverse events 16. Thrombotic risk would likely be related to the patient’s prothrombotic underlying disorder.  Similarly, for frozen plasma, thrombotic risk is poorly studied and risk is likely related to prothrombotic underlying disorders.

Desmopressin is occasionally used in patients with von Willebrand disease as it increases von Willebrand factor release from endothelial cells.  It has not been studied in anticoagulant-associated bleeding. A meta-analysis demonstrated no increased risk of thrombosis perioperatively when used for surgical patients 17.

Protamine sulfate is used to reverse the effects of unfractionated heparin, where there is a black box warning regarding the potential for hypersensitivity reactions in patients with fish allergies.  There have been reports of protamine-induced thrombocytopenia, notably after cardiac surgery, which can have similar features to heparin-induced thrombocytopenia including increased risk of thrombosis 18.

Case Conclusion

During the consent process, you explain the benefits as well as the risk of producing a blood clot to be less than 5% when reversing the anticoagulation with PCCs and vitamin K, much of that risk due to atrial fibrillation.  The patient and her family accept the treatment and the patient is seen by gastroenterology to have an endoscopy performed which stops the bleeding.

Upon discharge, upon reviewing risk factors of bleeding that could be controlled and discussing the discharge plan with the family physician, she notes the patient has not always been in target INR range because she has not always gotten bloodwork when she is supposed to.  The patient and her family currently do not want to start another anticoagulant such as a DOAC. You explain to the patient and her family the importance of getting follow up bloodwork to make sure the patient stays in the target INR.

Main Messages

  • The main risk of reversing anticoagulant is typically thrombosis, where much of the risk is due to the underlying prothrombotic state rather than the reversal agent itself
  • Thrombosis risks in different meta-analyses for warfarin reversal with PCCs +/- vitamin K are reported to be < 5%
  • The thrombosis risk after use of TXA is likely minimal, though most studies assessing its use in bleeding excluded patients with risk factors for thrombosis

Blood product or drug

Risk of Thrombosis
Prothrombin Complex Concentrates (PCCs) ·       1.4% (PMID 27488143)
·       2.7% (PMID 28540468)
·       4.1% (PMID 27488143)
PCCs to reverse factor Xa inhibitors ·       3/84 (4%) (PMID 2883543)
·       5/66 (8%) (PMID 29564837)
Activated Prothrombin Complex Concentrates (aPCCs) ·       in hemophilia patients is 4-8 per 105 infusions (PMID 11952842)
Recombinant Factor VIIa (rfVIIa)

 

·       significant increase in arterial thrombotic events reported from RCTs (RR 1.45) (PMID 22419303)
Tranexamic Acid (TXA)

 

·       268 RCTs demonstrated no thrombotic risk of TXA in perioperative trials (PMID 30516835)
Idarucizumab (antidote for dabigatran)

 

·       amongst 503 patients was about 5% and 7% at 30 and 90 days after reversal (PMID 28693366)
Andexanet Alfa (antidote for anti-Xa inhibitors) ·       24 thrombotic events in 228 patients (11%) (PMID 27573206)

Other Therapies

Vitamin K ·       does not have any intrinsic risk of producing thrombosis

·       meta-analysis of 21 studies had one study that assessed for adverse events (PMID 16505257)

Desmopressin ·       no increased risk of thrombosis perioperatively when used for surgical patients (PMID 19034103)
Protamine sulfate

 

·       protamine-induced thrombocytopenia, notably after cardiac surgery (PMID 273786030)

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

This post was reviewed by Teresa Chan, Sparsh Shah 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.
Brekelmans M, Ginkel K, Daams J, Hutten B, Middeldorp S, Coppens M. Benefits and harms of 4-factor prothrombin complex concentrate for reversal of vitamin K antagonist associated bleeding: a systematic review and meta-analysis. J Thromb Thrombolysis. 2017;44(1):118-129. [PubMed]
3.
Majeed A, Ågren A, Holmström M, et al. Management of rivaroxaban- or apixaban-associated major bleeding with prothrombin complex concentrates: a cohort study. Blood. 2017;130(15):1706-1712. [PubMed]
4.
Schulman S, Gross P, Ritchie B, et al. Prothrombin Complex Concentrate for Major Bleeding on Factor Xa Inhibitors: A Prospective Cohort Study. Thromb Haemost. 2018;118(5):842-851. [PubMed]
5.
Ehrlich H, Henzl M, Gomperts E. Safety of factor VIII inhibitor bypass activity (FEIBA): 10-year compilation of thrombotic adverse events. Haemophilia. 2002;8(2):83-90. [PubMed]
6.
Simpson E, Lin Y, Stanworth S, Birchall J, Doree C, Hyde C. Recombinant factor VIIa for the prevention and treatment of bleeding in patients without haemophilia. Cochrane Database Syst Rev. 2012;(3):CD005011. [PubMed]
7.
Ker K, Roberts I, Shakur H, Coats T. Antifibrinolytic drugs for acute traumatic injury. Cochrane Database Syst Rev. 2015;(5):CD004896. [PubMed]
8.
Perel P, Ker K, Morales U, Roberts I. Tranexamic acid for reducing mortality in emergency and urgent surgery. Cochrane Database Syst Rev. 2013;(1):CD010245. [PubMed]
9.
Bennett C, Klingenberg S, Langholz E, Gluud L. Tranexamic acid for upper gastrointestinal bleeding. Cochrane Database Syst Rev. 2014;(11):CD006640. [PubMed]
10.
Bryant-Smith A, Lethaby A, Farquhar C, Hickey M. Antifibrinolytics for heavy menstrual bleeding. Cochrane Database Syst Rev. 2018;4:CD000249. [PubMed]
11.
Yates J, Perelman I, Khair S, et al. Exclusion criteria and adverse events in perioperative trials of tranexamic acid: a systematic review and meta-analysis. Transfusion. 2019;59(2):806-824. [PubMed]
12.
Pollack C, Reilly P, van R, et al. Idarucizumab for Dabigatran Reversal – Full Cohort Analysis. N Engl J Med. 2017;377(5):431-441. [PubMed]
13.
Glund S, Moschetti V, Norris S, et al. A randomised study in healthy volunteers to investigate the safety, tolerability and pharmacokinetics of idarucizumab, a specific antidote to dabigatran. Thromb Haemost. 2015;113(5):943-951. [PubMed]
14.
Connolly S, Milling T, Eikelboom J, et al. Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors. N Engl J Med. 2016;375(12):1131-1141. [PubMed]
15.
Siegal D, Curnutte J, Connolly S, et al. Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity. N Engl J Med. 2015;373(25):2413-2424. [PubMed]
16.
Dezee K, Shimeall W, Douglas K, Shumway N, O’malley P. Treatment of excessive anticoagulation with phytonadione (vitamin K): a meta-analysis. Arch Intern Med. 2006;166(4):391-397. [PubMed]
17.
Crescenzi G, Landoni G, Biondi-Zoccai G, et al. Desmopressin reduces transfusion needs after surgery: a meta-analysis of randomized clinical trials. Anesthesiology. 2008;109(6):1063-1076. [PubMed]
18.
Bakchoul T, Jouni R, Warkentin T. Protamine (heparin)-induced thrombocytopenia: a review of the serological and clinical features associated with anti-protamine/heparin antibodies. J Thromb Haemost. 2016;14(9):1685-1695. [PubMed]
(Visited 475 times, 1 visits today)
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.
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
- 6 days ago