Anticoagulation Reversal

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Anticoagulation Reversal References

Vitamin K

Using Vitamin K and PCC per guideline recommendations reduces mortality Tazarourte, Karim, et al. “Guideline-concordant administration of prothrombin complex concentrate and vitamin K is associated with decreased mortality in patients with severe bleeding under vitamin K antagonist treatment (EPAHK study).” Critical Care 18.2 (2014): R81.

ACCP 2012 guidelines: Holbrook, Anne, et al. “Evidence-based management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.” Chest 141.2 Suppl (2012): e152S.

ACCP 2008 guidelines: Ansell, Jack, et al. “Pharmacology and Management of the Vitamin K AntagonistsAmerican College of Chest Physicians Evidence-Based Clinical Practice Guidelines.” CHEST Journal 133.6_suppl (2008): 160S-198S.

Editorial on IV versus Oral Vitamin K:  Shah, Neil, and Ravi Sarode. “Warfarin reversal: schism between clinical practice and published guidelines.” Transfusion 53.3 (2013): 476-479. 

Low dose oral vitamin K review: Wilson, Sarah E., Henry G. Watson, and Mark A. Crowther. “Low-dose oral vitamin K therapy for the management of asymptomatic patients with elevated international normalized ratios: a brief review.” Canadian Medical Association Journal 170.5 (2004): 821-824.

NEJM review of managing patients on anticoagulants undergoing invasive procedures:  Baron, Todd H., Patrick S. Kamath, and Robert D. McBane. “Management of antithrombotic therapy in patients undergoing invasive procedures.” New England Journal of Medicine 368.22 (2013): 2113-2124.

Oral versus IV Vitamin K: Watson, Henry G., et al. “A comparison of the efficacy and rate of response to oral and intravenous Vitamin K in reversal of over‐anticoagulation with warfarin.” British journal of haematology 115.1 (2001): 145-149.

Oral versus IV Vitamin K: Lubetsky, Aharon, et al. “Comparison of oral vs intravenous phytonadione (vitamin K1) in patients with excessive anticoagulation: a prospective randomized controlled study.” Archives of internal medicine 163.20 (2003): 2469.

Oral versus Subcutaneous Vitamin K: Crowther, Mark A., et al. “Oral vitamin K lowers the international normalized ratio more rapidly than subcutaneous vitamin K in the treatment of warfarin-associated coagulopathyA randomized, controlled trial.” Annals of internal medicine 137.4 (2002): 251-254.

Oral Vitamin K review: Crowther, Mark A., et al. “Treatment of warfarin-associated coagulopathy with oral vitamin K: a randomised controlled trial.” The Lancet 356.9241 (2000): 1551-1553.

Systematic review of coumarin coagulopathy treatment: Dentali, F., W. Ageno, and M. Crowther. “Treatment of coumarin‐associated coagulopathy: a systematic review and proposed treatment algorithms.”Journal of Thrombosis and Haemostasis 4.9 (2006): 1853-1863. 

Vitamin K Meta-analysis: DeZee, Kent J., et al. “Treatment of excessive anticoagulation with phytonadione (vitamin K): a meta-analysis.” Archives of internal medicine166.4 (2006): 391.

Vitamin K dosing: Tsu, Laura V., J. Erin Dienes, and William E. Dager. “Vitamin K dosing to reverse warfarin based on INR, route of administration, and home warfarin dose in the acute/critical care setting.” The Annals of pharmacotherapy 46.12 (2012): 1617-1626.

Cerebral Hemorrhage and Vitamin K Antagonists

Observational study of VKA ICH patients. Half given PCC and half . Rapid INR reversal with PCC . Getting PCC in quickly had benefit on ICH expansion. Kuwashiro, Takahiro, et al. “Effect of prothrombin complex concentrate on hematoma enlargement and clinical outcome in patients with anticoagulant-associated intracerebral hemorrhage.” Cerebrovascular Diseases 31.2 (2010): 170-176.

An observational study on ICH patients taking VKAs. The main conclusion one can draw from this paper is that VKA patients with ICH have a poor outcome. In this study, 76% composite end point of death of disability (mortality around 40%). Most patients were reversed and reversal didn’t seem to have an impact on outcome, but this was observational and not a controlled trial.  de Leciñana, M. Alonso, et al. “Questionable reversal of anticoagulation in the therapeutic management of cerebral haemorrhage associated with vitamin K antagonists.” Thromb Haemost 102.1 (2009): 42-48.

Steiner, T., et al. “Recommendations for the emergency management of complications associated with the new direct oral anticoagulants (DOACs), apixaban, dabigatran and rivaroxaban.” Clinical Research in Cardiology (2013): 1-14.

Horstmann, S., et al. “Intracerebral hemorrhage during anticoagulation with vitamin K antagonists: a consecutive observational study.” Journal of neurology (2013): 1-6.


Factor 7

Evidence based review on factor 7 and warfarin reversal: Rosovsky, Rachel P., and Mark A. Crowther. “What is the evidence for the off-label use of recombinant factor VIIa (rFVIIa) in the acute reversal of warfarin?.”ASH Education Program Book 2008.1 (2008): 36-38.

Factor 7 given to healthy patients on warfarin (improved lab tests but not bleeding time): Skolnick, Brett E., et al. “Exploratory study on the reversal of warfarin with rFVIIa in healthy subjects.” Blood 116.5 (2010): 693-701. 

Factor 7 vs PCC Chapman, Scott A., et al. “Comparison of 3-Factor Prothrombin Complex Concentrate and Low-Dose Recombinant Factor VIIa for Warfarin Reversal.” World Journal of Emergency Surgery 9.1 (2014): 27.


FEIBA vs FFP for warfarin reversal: Wójcik, Cezary, Michelle L. Schymik, and Eric G. Cure. “Activated prothrombin complex concentrate factor VIII inhibitor bypassing activity (FEIBA) for the reversal of warfarin-induced coagulopathy.” International journal of emergency medicine 2.4 (2009): 217-225.


PCC improves mortality Tilton, Ryan, et al. “Outcomes Associated With Prothrombin Complex Concentrate for International Normalized Ratio Reversal in Patients on Oral Anticoagulants With Acute Bleeding.” Annals of Pharmacotherapy (2014): 1060028014537897.

Four factor PCC versus FFP Circulation 2013: Sarode, Ravi, et al. “Efficacy and Safety of a 4-Factor Prothrombin Complex Concentrate in Patients on Vitamin K Antagonists Presenting With Major Bleeding A Randomized, Plasma-Controlled, Phase IIIb Study.” Circulation128.11 (2013): 1234-1243.

Using PCC to reverse NOACs (current evidence and lack thereof, 2014 publication): Dickneite, Gerhard, and Maureane Hoffman. “Reversing the new oral anticoagulants with prothrombin complex concentrates (PCCs): what is the evidence?.” Thromb Haemost (2014): 111.

PCC safety study (incidence of thromboembolic events 1.8% with 4 factor PCC and 0.7% with 3 factor PCC): Dentali, Francesco, et al. “Safety of prothrombin complex concentrates for rapid anticoagulation reversal of vitamin K antagonists.” Thrombosis and haemostasis 98.4 (2007): 790-797.

PCC safety studyMajeed, Ammar, et al. “Thromboembolic safety and efficacy of prothrombin complex concentrates in the emergency reversal of warfarin coagulopathy.”Thrombosis research 129.2 (2012): 146-151.

PCC versus FFP in the emergency dept (faster reversal, less transfusion, fewer adverse events with PCC compared with FFP): Hickey, Michael, et al. “Outcomes of Urgent Warfarin Reversal Using Fresh Frozen Plasma versus Prothrombin Complex Concentrate in the Emergency Department.” Circulation (2013).

PCC Dosing Study (higher dose gets INR down faster but no difference was found in outcome or adverse events): Kerebel, Delphine, et al. “A French multicenter randomised trial comparing two dose-regimens of prothrombin complex concentrates in urgent anticoagulation reversal.” Critical Care 17.1 (2013): R4.

PCC Review (how it’s made, heparin is added to keep factors from activating, discussion of half lives, adverse events, indications): Franchini, Massimo, and Giuseppe Lippi. “Prothrombin complex concentrates: an update.” Blood Transfusion 8.3 (2010): 149.

Beriplex experience at a tertiary hospital: Bruce, David, and T. J. Nokes. “Prothrombin complex concentrate (Beriplex P/N) in severe bleeding: experience in a large tertiary hospital.” Crit Care 12.4 (2008): R105.

Beriplex efficacy and safety study in patients bleeding or needing procedures: Pabinger, I., et al. “Prothrombin complex concentrate (Beriplex® P/N) for emergency anticoagulation reversal: a prospective multinational clinical trial.”Journal of Thrombosis and Haemostasis 6.4 (2008): 622-631.

Timing of FFP in treating ICH: Goldstein, Joshua N., et al. “Timing of fresh frozen plasma administration and rapid correction of coagulopathy in warfarin-related intracerebral hemorrhage.”Stroke 37.1 (2006): 151-155.

Dabigatran Reversal

Case Reports of  Successful Hemostasis Using PCC in Actively Bleeding Humans Schulman, Sam, et al. “Activated prothrombin complex concentrate for dabigatran‐associated bleeding.” British journal of haematology 164.2 (2014): 308-310.

PCC, FEIBA and Dabigatran Barron, Bridget. “The Effectiveness of Prothrombin Complex Concentrate in Reversing the Anticoagulant Activity of the Oral Director Thrombin Inhibitor Dabigatran (Pradaxa®): A Review of Human Studies.” (2013).

Dialysis Case Report: Warkentin, Theodore E., et al. “Recombinant factor VIIa (rFVIIa) and hemodialysis to manage massive dabigatran-associated postcardiac surgery bleeding.” Blood 119.9 (2012): 2172-2174.

Dialysis Case ReportEsnault, P., et al. “Haemodialysis before emergency surgery in a patient treated with dabigatran Br. J. Anaesth.(2013) 111 (5): 776-777 first published online May 5, 2013 doi: 10.1093/bja/aet160.”

Editorial on reversal: van Ryn, Joanne, et al. “Dabigatran etexilate-a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity.” Thrombosis & Haemostasis 103.6 (2010): 1116.

Oral Xa Reversal

R antidote (review of current research on a direct reversal agent for oral Xa inhibitors. it may also work for LMWH): Yeh, Calvin H., James C. Fredenburgh, and Jeffrey I. Weitz. “The Real Decoy An Antidote for Factor Xa–Directed Anticoagulants.” Circulation research 113.8 (2013): 954-957.

PCC improved lab tests in healthy rivaroxaban volunteers (but not dabigatran): Eerenberg, Elise S., et al. “Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate a randomized, placebo-controlled, crossover study in healthy subjects.” Circulation 124.14 (2011): 1573-1579.

PCC improved bleeding time in rivaroxaban rats: Perzborn, Elisabeth, et al. “Prothrombin complex concentrate reverses the effects of high-dose rivaroxaban in rats.” J Thromb Haemost 7.suppl 2 (2009): 379.

PCC and factor 7 improved lab tests but not bleeding in rivaroxaban rabbits: Godier, A., et al. “Recombinant activated factor VII efficacy and safety in a model of bleeding and thrombosis in hypothermic rabbits: a blind study.”Journal of Thrombosis and Haemostasis 5.2 (2007): 244-249.

FEIBA and factor 7 tested in rivaroxaban primates with improvement of bleeding time: Gruber, Andras, et al. “Potential of activated prothrombin complex concentrate and activated factor VII to reverse the anticoagulant effects of rivaroxaban in primates.” practice 2 (2008): 3.

FEIBA partially reverses rivaroxaban bleeding and PT in rats: Perzborn, Elisabeth, and Hanna Tinel. “FEIBA reverses the effects of a high dose of rivaroxaban in rats.” Pathophysiol Haemost Thromb 36.Suppl 1 (2008): A40.

Kaatz, Scott, et al. “Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors.” American journal of hematology 87.S1 (2012): S141-S145.

Editorial on NOAC reversal 2013: Battinelli, Elisabeth M. “Reversal of new oral anticoagulants.” Circulation124.14 (2011): 1508-1510.

PCC reversal of Edoxaban Brown, Karen, et al. “THE IMPACT OF PROTHROMBIN COMPLEX CONCENTRATE ON THE ANTICOAGULATORY EFFECTS OF EDOXABAN.” Journal of the American College of Cardiology 63.12_S (2014).

Zahir, Hamim, et al. “Edoxaban Effects on Bleeding Following Punch Biopsy and Reversal by a 4-Factor Prothrombin Complex Concentrate.” Circulation(2014): CIRCULATIONAHA-114.

Herzog, E., et al. “Reversal of edoxaban-induced anticoagulation by the four-factor prothrombin complex concentrate Beriplex® in a rabbit model.” Critical Care 18.Suppl 1 (2014): P98.

Reversal Reviews

Lab monitoring and reversal options for NOACsMiyares, Marta A., and Kyle Davis. “Newer oral anticoagulants: a review of laboratory monitoring options and reversal agents in the hemorrhagic patient.”American Journal of Health-System Pharmacy 69.17 (2012): 1473-1484.

Australasian Warfarin reversal guidelines 2004: Baker, Ross I., et al. “Warfarin reversal: consensus guidelines on behalf of the Australasian Society of Thrombosis and Haemostasis.” Medical Journal of Australia 181.9 (2004): 492-497.

Review on Xa, thrombin inhibitors and VKA reversal in patients with ICH: James, Robert F., et al. “The role of anticoagulants, antiplatelet agents, and their reversal strategies in the management of intracerebral hemorrhage.”Neurosurgical focus 34.5 (2013): E6.



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