Author: Erica Simon, DO, MHA (EM Resident Physician, SAUSHEC) // Edited by: Alex Koyfman, MD (EM Attending Physician, UT Southwestern Medical Center / Parkland Memorial Hospital, @EMHighAK) & Justin Bright, MD (@JBright2021)

It’s a busy night in the ED. You’re paged to the trauma bay with the report of an incoming elderly male, found down in his home, and intubated in the field secondary to agonal respirations. EMS arrives and reports Afib on initial rhythm strip, peripheral IV access, and the absence of post-intubation sedation.

C-collar is in place. ABCs are intact; BP 188/99, HR 58, GCS 3T. HEENT reveals non-reactive pupils: the right 4mm, the left 1mm; and a hematoma localized to the right posterior parietal area. Labs are sent. You quickly initiate treatment for suspected increased ICP. As the patient’s trauma scan is nearly complete, the med tech calls to inform you of an INR of 8.3. CT reveals a large subdural hematoma. Neurosurgery is paged.

You quickly change your focus to reversing the patient’s INR. You suspect that he takes Coumadin. What should you do? Order FFP? PCC? Factor VIIa?

Background

Nearly 65,000 patients visit U.S. emergency departments annually for anticoagulant related hemorrages.1 Despite this staggering amount, the aforementioned figure does not reflect adverse bleeding events associated with Direct Thrombin Inhibitors (DTIs) and Factor Xa Inhibitors.

As EM Docs, it goes without saying that we need to know what to do to address these potentially life-threatening bleeds, so, let’s take a look at the commonly prescribed oral anticoagulants, their mechanisms of action, their pharmacokinetics, and recommendations for their reversal.

Here’s a bit of a visual refresher to reference throughout the discussion:

Vitamin K Antagonists:

Coumadin (Warfarin)

Indications



In the United States, Coumadin is indicated for the prophylaxis and treatment of VTE, PE, thromboembolic complications associated with a.fib or cardiac valve replacement, and for reduction of mortality risk secondary to recurrent MI, embolizations s/p MI and CVAs.3

Mechanism of Action

Coumadin acts through the inhibition of vitamin K epoxide reductase, ultimately limiting the synthesis of Factors II, VII, IX, and X, and the anticoagulant proteins C and S. Therapeutic doses of warfarin decrease the total amount of the active form of each vitamin K dependent clotting factor by approximately 30%-50%. 3

Pharmacokinetics

Coumadin’s effect generally occurs within 24 hours s/p administration, with peak anticoagulation seen at 72-96 hours.3 PT and INR are measures of the extrinsic pathway of the coagulation cascade, and are therefore utilized to monitor Coumadin’s anticoagulation effect. The duration of action of a single dose of Coumadin ranges from 2-5 days. Coumadin undergoes hepatic cytochrome metabolism, exhibits 97% plasma protein binding, and is renally eliminated.4

Mechanisms for Reversal

Vitamin K – As mentioned above, vitamin K is an essential cofactor in the synthesis of factors II, VII, IX, X and proteins C and S. All patients who are actively bleeding should receive 5-10mg of IV vitamin K by slow infusion.5,6 The time to onset is often 2-6 hours. Greater than 24 hours are needed to achieve an effective response, therefore other methods of reversal must be utilized in the interim (see below).6

Be aware: anaphylactic reactions to IV vitamin K occur in 3 out of every 10,000 doses. This reaction is most commonly secondary to the diluent in which the vitamin K is prepared.5 In addition, providers need to appreciate that vitamin K administration causes a permanent reversal of existing clotting factors, and adequate re-anticoagulation cannot be achieved for nearly 2 weeks.

Fresh frozen plasma (FFP) – FFP contains all coagulation factors in a non-concentrated form. FFP is type specific, with individuals of the AB blood type being universal donors. As you might expect, risks associated with transfusion include blood-borne infections and allergic reactions. FFP administration is limited secondary to the product’s frozen storage, often requiring 15-20 minutes to thaw. 7 In addition, large volumes of FFP (10-15 ml/kg) may be required to address serious hemorrhages, making this reversal agent less than ideal in patients suffering from a. fib, cardiac valvular disease, and ventricular dysfunction (significant increases in intravascular volume could result in decompensated heart failure). 8

How many units of FFP are recommended as a starting point? Most resources cite 2 U for isolated intracranial bleeds and 4 U for extracranial hemorrages.9 Where do these numbers come from?

It is generally accepted that one unit of FFP corrects clotting factors by 2.5-5% in a 70kg individual. To experience a significant change in clotting status, clotting factor levels must increase by at least 10%. If we assume that one unit of FFP increases clotting factor levels by 5%, then 2 U must be used to achieve 10%. If we assume one unit increases clotting factor levels by 2.5%, then 4 Units of FFP must be used to achieve 10%.9

Prothrombin Complex Concentrate (PCC) – This portion of the talk references 4-Factor PCC (we’ll address 3-Factor PCC shortly). 4-Factor PCC contains activated factor VII, and non-activated factors II, IX, and X. Proteins C and S are also thrown in the mix with heparin and AT3 (to keep the non-activated factors inactive). Available in the US: Kcentra.

Kcentra is indicated for the urgent reversal of acquired coagulation factor deficiency induced by vitamin K antagonists in the setting of acute major bleeding. Kcentra dosing varies according to the patient’s baseline INR and body weight (initial dose recommended as 25-50 IU/kg for significant bleeds). PCC is contraindicated in patients with DIC and HIT as thromboembolic events are the most serious adverse reactions encountered.10,11

FFP vs. PCC, is one mechanism of reversal superior to the other?

Currently there is one trial to date directly comparing FPP and PCC in the reversal of vitamin K antagonists:

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.” Circulation. 2013. 128:1234-1243.

This trial randomized 202 patients with hemorrhage secondary to Vitamin K antagonists to FFP or PCC treatment arms. All patients received IV vitamin K.

Results: PCC corrected INR faster than FFP (Probably not surprising as PCC can be prepared and run in faster than FFP and as we will discuss below, PCC delivers much more bang for the buck in terms of volume/clotting factor delivered.) At 24 hours, INR was similar in both groups. Thromboembolic events were statistically the same for both groups: 7.8% PCC and 6.4% FFP, and death rates were comparable between the two groups. (Patient oriented outcomes, except death, were not studied).

How do FFP and PCC compare in terms of the volume required for anticoagulation reversal?

In his “Reversal of Anticoagulation” lecture posted on ERCAST.ORG, Robert Orman gave a great volume calculation example:

There is some variability in the quantity of each factor in individual vials of PCC, but utilizing Factor IX, the chosen standard measurement, each 500 unit vial of 4-Factor PCC is equivalent to 2 units of FFP. So, in an 80 kg individual with an INR of 10, utilizing recommended reversal doses of 50 IU/kg of PCC and 15 cc/kg FFP:

15 cc/kg FFP = 1200cc = 1200 Units of factor

50 IU/kg PCC = 4000 units of factor = 8 vials (equivalent to 4 L of FFP)

In order to achieve the amount of clotting factors in 8 vials of PCC, it would take 4 liters (16 BAGS) of FFP.9

How do FFP and PCC compare in terms of cost?

The average wholesale cost of PCC is $2.17/IU.10 Utilizing the recommended dosing of 50 IU/kg, this equates to $108.50 per patient kg. As an example, for our 80 kg patient this is $8,680. As of 2011, the mean cost of one unit of FFP across US teaching hospitals was $60.70 ± $20.12 Taken at it’s most expensive, and starting with the recommended transfusion dose of 4 Units, this equates to $322.80.

Back to the topic at hand: bottom line in reversing a vitamin K antagonist:

– Give IV Vitamin K à 10-15mg IV

FFP is an option à 15ml/kg, start with 2-4 Units; caution in patients with CHF, Afib, and valvular disorders 2/2 volume

PCC = Costly, but less volume, more factor, faster time to INR reversal à 25-50 IU/kg

The more you know: The American College of Chest Physicians currently recommends rapid reversal of anticoagulation with 4-factor prothrombin complex concentrate rather than with plasma for patients with vitamin K antagonist associated hemorrhage.14

What about 3-Factor PCC you ask? 3-Factor PCC is available in the US as Bebulin and Profilnine. These concentrates are FDA approved specifically for the treatment of bleeding events in individuals with hemophilia B (Factor IX deficiency).15,16 All other uses are off-label, thus little data exists to support or defend their utilization in the setting of anticoagulant associated hemorrhages.

Direct Thrombin Inhibitors (DTIs):

Dabigatran (Pradaxa), Argatroban (Novastan), Ximelagatran and Melagatran (Exanta), Lepirudin (Refludan), Desirudin (Iprivask), and Bivalirudin (Hirulog)

Indications

DTIs are used for prophylaxis and treatment of VTE and ACS, and for prophylaxis of thrombus formation in non-valvular a.fib. They are also used as anticoagulation alternatives in the setting of HIT. Dabigatran, the most commonly prescribed oral DTI, is approved for treatment of VTE in patients treated with concomitant parenteral anticoagulation for at least five days, and for the treatment of thrombus secondary to non-valvular a.fib.17

Mechanism of Action

DTIs are potent inhibitors of both free thrombin and clot-bound thrombin. (Reference the handy clotting cascade figure above for a quick review). Given this mechanism of action, both the thrombin time and ecarin clotting time can be utilized to measure drug effects. As these laboratory studies are not widely available, they are of little utility in the emergency setting. In terms of dabigatran, studies have indicated that a PTT > 40 can qualitatively indicate activity, but no quantitative assay exists.18

Extra Credit, i.e. more than you would ever want to know about a hematological test à

Ecarin time measures the production of meizothrombin, an intermediary in the conversion of prothrombin to thrombin. 19

Pharmacokinetics

Pharmacokinetics vary based upon inhibitor:

Mechanisms for Reversal

At this point in time, there are no specific reversal agents available for the DTIs. The American College of Cardiology Foundation and the American Heart Association recommend transfusion of packed red blood cells and FFP, in addition to surgical intervention (DTIs have been associated w intracranial and GI hemorrhage), to control bleeding.21, 22 However, given that FFP contains factor II, which is inhibited from activation by DTIs, the use of FFP may only be minimally beneficial.23 For patients with impaired renal function who have life-threatening bleeding following dabigatran-induced coagulopathy, hemodialysis has been recommended as dabigatran possesses characteristically low plasma protein binding (approximately 35%), making it easily dialyzable.24 Others have suggested that in the event of significant bleeding, the use of a 4-factor PCC may be the most effective option; however, there is limited evidence-based data (majority of studies are of dabigatran – see below).22

On the horizon: An antibody to dabigatran, Anti-Dabi-Fab. This antibody is highly specific for dabigatran, allowing it to bind the antibody instead of thrombin.31

Reversal Strategy Animal Studies (Dabigatran-Treated Animals) Ex Vivo Studies (Dabigatran-Treated Healthy Volunteers or Patient) Ex Vivo Studies (Dagibatran and Reversal-Agent Treated Healthy Volunteers) Non-Specific Reversal Agents 4-Factor PCC No reduction in blood loss after tail transection in mice.23 Corrected some TG indices in dagibatran-treated healthy volunteers.27 No correction of aPTT, ECT, TT.29 Reduced intracranial hematoma expansion and 24 hour mortality in mice.25 Corrected PT, aPTT, TT and some TG indices in dabigatran treated patients, but demonstrated no correction of Hemoclot assay in dabigatran-treated patients.28 Reduced blood loss following kidney incision in rabbits.26 Specific Reversal Agents Anti-Dabi-Fab Reduced blood loss after tail transection and corrected dilute PT assay.30

Evidence for reversal of Dabigatran (Adapted)24

Abbreviations: Anti-Dabi-Fab, humanized monoclonal antibody fragment against dabigatran; aPTT, activated partial thromboplastin time; ECT, ecarin clotting time; PCC, prothrombin complex concentrate; PT, prothrombin time; TG, thrombin generation; TT, thrombin time.

Bottom line:

American College of Cardiology Foundation and AHA à Reverse DTIs with PRBCs and FFP

Dabigatran à Case reports demonstrate benefit from hemodialysis

4-Factor PCC à Potential role (studied in dabigatran), but no great EBM at this point

Direct reversal agent is in the works

Factor Xa Inhibitors:

Rivaroxaban (Xarelto), Apixaban (Eliquis), Fondaparinux (Arixtra)

Indications

Factor Xa inhibitors are used for prophylaxis and treatment of VTE, as well as for prophylaxis of embolic disease in non-valvular a.fib, and as an alternative anticoagulant in the setting of HIT.24

Mechanism of Action

These drugs inhibit factor Xa, the first step in the common pathway, either directly or indirectly (Again, reference the clotting cascade figure above). The inhibition of factor Xa occurs in a dose-dependent manner.24 Apixaban and rivaroxiban, directly bind to the active site of factor Xa, thereby inhibiting both free and clot-associated factor Xa. Indirect inhibitors (fondaparinux) bind to AT3, resulting in a conformational change, thereby inhibiting factor Xa. The activity of these medications can be directly monitored through the utilization of anti-factor Xa laboratory studies.

Pharmacokinetics

Factor Xa Inhibitors Feature Rivaroxaban Apixaban Fondaparinux Bioavailability 80% 50% 100% Time to Peak 2-3 Hours 3 Hours 3 Hours Half-life 7-11 Hours 8-14 Hours 17-21 Hours Excretion Renal Feces Renal Plasma Protein Binding 95% 87% 94%

Pharmacokinetics of Factor Xa Inhibitors3, 33

Mechanisms for Reversal

Currently, there are no specific reversal agents for Factor Xa inhibitors. Although EBM is limited, 4-Factor PCC has shown promising results in studies utilizing rivaroxaban (see chart below).

A recombinant factor Xa derivative (PRT064445; Portola Pharmaceuticals, San Francisco, CA, USA) currently in development as a specific factor Xa inhibitor reversal agent. This protein binds factor Xa inhibitors, limiting their effect on endogenous factor Xa. Preliminary results of an ongoing Phase II, randomized, double-blind trial in healthy volunteers (apixaban 5 mg twice daily, 11 doses) showed that PRT064445 decreased anti-Xa activity and reduced plasma concentrations of free apixaban compared with placebo.35

Reversal Strategy Animal Studies (Factor Xa Inhibitor-Treated Animals) Ex Vivo Studies (Factor Xa Inhibitor-Treated Healthy Volunteers or Patient) Ex Vivo Studies (Factor Xa and Reversal-Agent Treated Healthy Volunteers) Non-Specific Reversal Agents (Effect on Rivaroxaban) PCC Corrected aPTT33 Corrected PT27 Corrected PT25 Variably corrected PT33, 34 Variably corrected TG indices26, 27 No reduction of blood loss in rabbits.33 No correction of anti-Xa activity27 Reduced bleeding time in rats but not primates.34 Specific Reversal Agent Rivaroxaban Apixaban PRT064445 Corrected INR, PT, aPTT, anti-Xa activity.35 Reduced blood loss. Corrected INR, PT, aPTT, anti-Xa activity.35

Evidence for Reversal of Anti-Factor Xa (Adapted) 24

Abbreviations: aPTT, activated partial thromboplastin time; INR, international normalized ratio; PCC, prothrombin complex concentrate; PT, prothrombin time.

Bottom Line:

4-Factor PCC à Potential role (studied in Rivaroxaban); shows promise

Specific reversal agent, PRT064445 is on its way

If you’ve read this far, you might be thinking to yourself: “Wait, you didn’t talk about Factor VIIa?”

Recombinant factor VIIa was developed to address bleeding complications in hemophilia patients with inhibitors. Use of rFVIIa outside its approved indication has been associated with an increased risk of arterial thromboembolism as compared with placebo (5.5% vs 3.2%; relative risk 1.68; 95% confidence interval (CI) 1.20–2.36).36

For extra reading on rFVIIa see:

Levi M, et al. Safety of recombinant activated factor VII in randomized clinical trials. N Engl J Med. 2010; 363:1791–1800.

References / Further Reading

Shehab N, Sperling LS, Kegler SR, et al. National estimates of emergency department visits for hemorrhage-related adverse events from clopidogrel plus aspirin and from warfarin. Arch Intern Med. 2010; 170:1926–33. Fawole A, Crowther M, Daw H. Practical management of bleeding due to the anticoagulants dabigatran, rivaroxaban, and apixaban. CCJM. 2013; 80(7): 443-451. “COUMADIN® TABLETS (Warfarin Sodium Tablets, USP) Crystalline COUMADIN® FOR INJECTION (Warfarin Sodium for Injection, USP): Anticoagulant.” Medication Guide. U.S. Food and Drug Administration, 2010. Web. 18 Sept. 2015. <http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/009218s108lbl.pdf>. Gonsalves W, Pruthi R, Patnaik M. The new oral anticoagulants in clinical practice. Mayo Clin Proc. 2013; 88(7): 777. Bechtel B, Nunez T, Lyon J, Cotton B, Barrett T. Treatments for reversing warfarin anticoagulation in patients with acute intracranial hemorrhage: a structured literature review. Int J Emerg Med. 2011; 4:40. Steiner T, Rosand J, Diringer M. Intracerebral hemorrhage associated with oral anticoagulant therapy. Stroke. 2006; 37: 256–262. Hickey M, Gatien M, Taljaard M, Aujnarain A, Giulivi A, et al. Outcomes of urgent warfarin reversal with frozen plasma versus prothrombin complex concentrate in the emergency department. Circulation. 2013; 128(4): 360-364.

8. Appelboam R, Thomas EO. Warfarin and intracranial haemorrhage. Blood Rev. 2009; 23:1–9. doi: 10.1016/j.blre.2008.05.001. Orman, R. (2014). Anticoagulation Reversal. 2014. Web 18 Sept 2015. <http://blog.ercast.org/wp-content/uploads/2013/12/Anticoagulation-Reversal-Handout-12312013.pdf?57bf90> Awad N, Cocchio C. Activated prothrombin complex concentrates for reversal of anticoagulant-associated coagulopathy. P T. 2013; 38(11): 696-698, 701. “Prothrombin Complex Concentrate (Human), Kcentra.” Medication Guide. U.S. Food and Drug Administration. 2010. Web. 18 Sept. 2015 http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/UCM350239.pdf>. Toner R, Pizzi L, Leas B, Ballas S, Quigley A, Goldfarb N. Costs to hospitals of acquiring and processing blood in the US: a survey of hospital-based blood banks and transfusion services. Appl Health Econ Health Policy. 2011; 9(1): 29-37. 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.” Circulation. 2013; 128: 1234-1243. Guyatt G, Akl E, Crowther M, Gutterman D, Schunemann H. Antithrombotic therapy and prevention of thrombosis 9th ed: American college of chest physicians evidence-based clinical practice guidelines. Chest. 2012; 141(2): 7S-47S. “Bebulin (Factor IX Complex), Nanofiltered and Vapor Heated. Medication Guideˆ. Baxter Healthcare Corporation. 2012. Web. 20 Sept. 2015. <http://www.baxalta.com/assets/documents/bebulin_pi.pdf> “Profilnine.” Medication Guide. U.S. Food and Drug Administration. 2010. Web. 20 Sept. 2015. <http://www.fda.gov/ucm/groups/fdagov-public/@fdagov-bio-gen/documents/document/ucm261964.pdf.> Harter K, Levine M, Henderson S. Anticoagulation drug therapy: a review. West J Emerg Med. 2015; 16 (1): 11-17. Van Ryn J, et al. “Dabigatran etexilate-a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity.” Thrombosis & Haemostasis2010; 103(6): 1116. Nowak G. The ecarin clotting time, a universal method to quantify direct thrombin inhibitors. Pathophysiol Haemost Thromb. 2003; 33(4): 173-83. Di Nisio M, Middledorp S, Buller H. Direct thrombin inhibitors. N Engl J Med. 2005. 353 (26): 2827. Wann L, Curtis A, Ellenbogen K, Estes N, Ezekowitz M, et al. 2011 ACCF/AHA/HRS Focused Update on the Management of Patients With Atrial Fibrillation (Update on Dabigatran). J Am Coll Cardiol. 2011; 57(11):1330-7 22. Levine M, Goldstein J. Emergency reversal of anticoagulation: novel agents. Curr Neurol Neurosci Rep. 2014 in press. Ganetsky M, Babu KM, Salhanick SD, et al. Dabigatran: review of pharmacology and management of bleeding complications of this novel oral anticoagulant. J Med Toxicol. 2011; 7:281–7

24. Siegal D, Cuker A. Reversal of target-specific oral anticoagulants. Drug Discov Today. 2014; 19(9): 1465-1470. Lambourne MD, et al. Prothrombin complex concentrates reduce blood loss in mice rendered coagulopathic by warfarin but not dabigatran etexilate. Transfusion. 2012; 52: 56A–57A. Zhou W, et al. Hemostatic therapy in experimental intracerebral hemorrhage associated with the direct thrombin inhibitor dabigatran. Stroke. 2011; 42: 3594–3599. Pragst I, et al. Reversal of dabigatran anticoagulation by prothrombin complex concentrate (Beriplex P/N) in a rabbit model. J Thromb Haemost. 2012; 10: 1841–1848. Marlu R, et al. Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban. A randomised crossover ex vivo study in healthy volunteers. Thromb Haemost. 2012; 108: 217–224. Herrmann R, et al. Thrombin generation using the calibrated automated thrombinoscope to assess reversibility of dabigatran and rivaroxaban. Thromb Haemost. 2014; 111: 989–995. Eerenberg ES, et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2011; 124: 1573–1579. Mattu A, Smith S, Lugassy D. Clinical toxicology. Emerg Med Clin. 2014; 32(1): 1-276. Donat F, Duret J, Santoni A, Cariou R, Necciari J, et al. The pharmacokinetics of fondaparinux sodium in healthy volunteers. Clin Pharmacokinet. 2002; 41 Suppl 2:1-9.

33. Godier A, et al. Evaluation of prothrombin complex concentrate and recombinant activated factor VII to reverse rivaroxaban in a rabbit model. Anesthesiology. 2012;116:94–102. Perzborn E, et al. Reversal of rivaroxaban anticoagulation by haemostatic agents in rats and primates. Thromb Haemost. 2013;110:162–172. 35. Lu G, et al. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med. 2013;19:446–451. Levi M, et al. Safety of recombinant activated factor VII in randomized clinical trials. N Engl J Med. 2010;363:1791–1800. http://www.ncbi.nlm.nih.gov/pubmed/26149803 http://www.ncbi.nlm.nih.gov/pubmed/25918557