anticoagulation, reversal, hemorrhage, hemorrhagic, shock, warfarin, coumadin, PCC, vitamin K, FFP, coagulopathy, coagulation, Kcentra

1. +
Management of Emergent
Warfarin Coagulopathy
Zach Jarou
Michigan State University

2. +
Warfarin
 used to prevent thromboembolism for >50 years
 atrial fibrillation
 prosthetic heart values
 venous thromboembolism
 narrow therapeutic window
 requires regular INR checks
 3-7% patients are at risk of major, life-threatening bleeding
 mechanism of action = vitamin K antagonist

3. +
Coagulation Cascade

4. +
Common Reversal Agents
 Vitamin K
 Fresh Frozen Plasma (FFP)
 Prothrombin Complex Concentrates (PCC)
 3-factor
 4- factor
Choice of Reversal Agents & Dosing is Based on INR!

5. +
Vitamin K
 fat soluble vitamin required for post-translational modification of
proteins required for blood coagulation & other pathways
 types
 K1 = synthesized by plants for use in photosynthesis; highest levels in
green leafy vegetables
 K2 = main storage form in animals, bacteria in the colon lengthen the
isoprenoid side change to create a range of subtypes
 routes & dosing
 5 < INR < 9 (no significant bleeding), give 1  2.5 mg PO q24
 INR > 9 (no significant bleeding), give 2.5  5 mg PO q24-48
 significant bleeding, 10 mg IV (slow to prevent allergic reaction)
 administer lowest dose possible to prevent refractoriness to
warfarin once restarted

6. +
Fresh Frozen Plasma (FFP)
 fluid portion of one unit of blood that has been centrifuged,
separated, and frozen solid at -18°C or colder within 8 hours of
collection  has to thaw & has large volume
 labile & stable components of coagulation, fibrinolytic, complement
systems; oncotic & immunologic proteins; other proteins, fats,
carbohydrates, minerals
 use has increased ten-fold over the past decade (possible related
to decreased availability of whole blood due to widespread
acceptance of component therapy)
 risks include: disease transmission, anaphylactoid reactions,
alloimmunization, excessive intravascular volume, transfusion
related lung injury (TRALI)
 must ensure compatibility with type & match

7. + Prothrombin Complex Concentrates (PCCs)
Am J Health-Syst Pharm. 2013; 70(Suppl 1):S12-21
=
 prepared from FFP  factors II, VII, IX, X
 3-factor is low in VII, 4-factor is high in VII
 risk of pro-thrombotic potential, especially with activated products

8. + Choice of Reversal Agents is Based on INR
and/or Presence of Significant Bleeding
CHEST 2008; 133:160S–198S (American College of Chest Physicians)

9. +
Kcentra Receives FDA Approval in 2013,
Prepare For an Onslaught of Ads
 first 4-factor PCC approved for us in the United States
 marketed as Beriplex in 25 other countries
 alternative to making your own by adding rVIIa to 3-factor PCC

10. +
So, which is best? FFP or PCC?
Circulation. 2013;128:360-364
This is the first study comparing the use of FFP vs. PCC in
the Emergency Department.

11. +
Methods & Study Design
 two tertiary care EDs in Canada (total ~120k visits per year)
 retrospective, before-after study (2 years with FFP; 2 years with
Octaplex, a 4-factor PCC)
 inclusion = 18 years or older, on warfarin with INR > 1.5,
received Octaplex or FFP in ED
 exclusion = <18 years old, no warfarin documentation, no pre-
treatment INR check, both Octaplex and FFP given within 7
days
 314 patients (FFP = 149, Octaplex = 165)

12. +
Study Enrollment
Circulation. 2013;128:360-364

13. +
Outcome Measures
 Primary (adverse outcomes within 7 days)
 death
 ischemic stroke
 myocardial infarction
 congestive heart failure
 venous thromboembolism
 peripheral arterial thromboembolism
 Secondary
 time to INR reversal
 mean hospital length of stay
 number of units of pRBCs transfused within 48 hours

14. +
Baseline Characteristics & PMH

15. +
Reason for Anticoagulation

16. +
Reason for Reversal

17. +
Primary Outcomes: Adverse Events

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Secondary Outcomes

19. + Multivariable Regression to Obtain Adjusted
Relative Risk of Adverse Events

20. +
Limitations
 retrospective data collection
 only 7 day follow up
 more FFP patients with history of CHF
 more FFP patients needed urgent reversal for ICH
 more PCC patient treated for pre-procedure
 unblinded outcome adjudication (although strict definitions of
each adverse event were established a priori)

21. +
Conclusions
 PCC can be administered quickly (no thaw time)
 PCC requires less infusion volume
 compared to FFP, administration of PCC led to:
 quicker INR reversal
 fewer RBC transfusions
 fever adverse events
 but remember, the only FDA-approved indication for 4-factor
PCCs is life-threatening bleeding on warfarin

22. +
References
 Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palaretti
G. Pharmacology and Management of the Vitamin K
Antagonists. Antithrombotic and Thrombolytic Therapy 8th Ed:
ACCP Guidelines. CHEST. 2008; 133:160S-198S.
 Hickey M, Gatien M, Taljaard M, Aujnarain A, Giulivi A, Perry
JJ. Outcomes of Urgent Warfarin Reversal With Frozen Plasma
Versus Prothrombin Complex Concentrate in the Emergency
Department. Circulation. 2013; 128:360-364.
 Kalus JS. Pharmacologic interventions for reversing the effects
of oral anticoagulants. Am J Health-Syst Pharm. 2013; 70
(Suppl 1):S12-21.

23. +
Thank you!
Zach Jarou
Michigan State University