This document summarizes questions from an audience regarding reversal of anticoagulation. It discusses the costs and doses needed for fresh frozen plasma to reverse a coumadin-associated life-threatening bleed. It also reviews products available at Advocate Christ Medical Center for reversing oral anticoagulants, and presents two clinical cases involving patients on Pradaxa and Rivaroxaban with bleeding complications. The document then reviews the coagulation cascade and how different anticoagulants act within it. It evaluates reversal agents for different anticoagulants including PCCs, FEIBA, activated factor VIIa, and provides dosing and safety information for each. Recommendations are given for reversing specific ant

1. David Barounis
R-2
Advocate Christ Medical Center

2. Some Questions to the
Audience
1. How much does FFP cost and how
much do you need to give in reversal of
coumadin associated life threatening
bleed??

3. Some Questions to the
Audience
1. How much does FFP cost and how
much do you need to give in reversal of
coumadin associated life threatening
bleed??
A: $1/ml, typically need 4U for reversal
with 250cc/unit = $1000.
1. What other products are available here
at christ hospital for reversal of oral
anticoagulants?

4. Case 1
1. 65y/o F with A-fib presents on Pradaxa
presents with an ICH approximately
25cc volume with no significant shift.
What’s you next move??

5. Case 2
 58y/o M s/p total hip replacement on
rivaroxaban for DVT prophylaxis
presents with lightheadness and
weakness. Hgb is 4.2 guaic negative
from below.
 Where is the bleed?

6. Case 2
 58y/o M s/p total hip replacement on
rivaroxaban for DVT prophylaxis
presents with lightheadness and
weakness. Hgb is 4.2 guaic negative
from below.
 Where is the bleed?
 CT A/P: Large retroperitoneal hematoma

7. Coagulation Cascade

8. Coagulation Cascade

9. The ER coagulation
cascade
Tissue Damage
OTHER FACTORS
V, VIII, IX, XI, XII
1.FACTOR VIIa
2.FACTOR Xa ==FACTOR X
3.PROTHROMBIN== THROMBIN
FIBRONGEN ==FIBRIN CLOTS

10. The ER coagulation
cascade
COUMADIN
Tissue Damage
OTHER FACTORS
V, VIII, IX, XI, XII
1.FACTOR VIIa
2.FACTOR Xa ==FACTOR X
3.PROTHROMBIN== THROMBIN
FIBRONGEN ==FIBRIN CLOTS

11. The ER coagulation
cascade
Tissue Damage
OTHER FACTORS
V, VIII, IX, XI, XII LOVENOX
1.FACTOR VIIa
AT III
HEPARIN 2.FACTOR Xa ==FACTOR X
3.PROTHROMBIN== THROMBIN
FIBRONGEN ==FIBRIN CLOTS

12. Dabigatran(Pradaxa)
 Direct Thrombin Inhibitor
 Approved for anti-coagulation in patients
with non-valvular atrial fibrillation
 RE-LY trial comparing coumadin to
Dabigatran

13. The ER coagulation
cascade
Tissue Damage
OTHER FACTORS
V, VIII, IX, XI, XII
1.FACTOR VIIa
2.FACTOR Xa ==FACTOR X
3.PROTHROMBIN== THROMBIN PRADAXA
FIBRONGEN ==FIBRIN CLOTS

14. Back to Case 1
 ICB in patient on pradaxa
 Step 1: What is the patients aPTT?
The PTT, typically 1.5X normal 12hours
after last dose. If < 32 seconds unlikely for
patient to have high enough blood
concentrations for benefit from reversal

15. Novel Reversal Agents
1. PCC
WE DO NOT HAVE PCC’s here at Christ
Hospital.
Cost is similar to 4U of FFP($1000 vs $1200)
USA 3 factor PCC’s only (does not contain high quantity
of factor VII)
So assuming 4U (1L) of FFP vs 2000U of Profilnine
Factor II: 1000U FFP : 2900U Profilnine
Factor IX: 1000U FFP : 2000U Profilnine
Factor VII: 1000U FFP: 700U Profilnine
Factor X: 1000U FFP : 1200U Profilnine

16. PCC’s Safety
*1.4% complication rate (3 CVA, 2 DVT, and 2 non Q wave MI’s)

17. The ER coagulation
cascade
Tissue Damage
OTHER FACTORS
V, VIII, IX, XI, XII
1.FACTOR VIIa
PCC’s 2.FACTOR Xa ==FACTOR X
3.PROTHROMBIN== THROMBIN PRADAXA
FIBRONGEN ==FIBRIN CLOTS

18. Are they effective in patients
with non-VKA?
Reversal of Rivaroxaban and Dabigatran by Prothrombin
Complex Concentrate. Circulation 2011
12 healthy volunteers: No effect of PCC on Dabigatran
reversal, completely reversed measured anticoagulation in
subjects receiving Rivaroxaban.
JUST REMEMBER THIS IS IN HEALTHY PT VOLUNTEERS
WITHOUT HEAD BLEEDS!!!

19. Activated Factor VIIa
(Novo7)
 Recommended by the makers of Dabigatran as
the “Reversal agent of choice”.
 Dose 90mcg/kg = 1mg
 Very short half life and often requires repeated
dosing ($1.13/mcg, usually need 1mg X 4 INITIAL
X 4 MAINTENCE OVER 4-6 HOURS= $55,000)

20. Safety of Novo7
 Thromboembolic Adverse Events (TAE)
249/3184 = 7.8% (placebo 6.2% RR 1.37)
*Arterial TAE OR 1.5 (95%CI 0.93-2.41)
Venous TAE OR 0.76 (95% CI 0.49-1.15)
*Trend toward statistical significance (>5%
incidence in the elderly > 65.)

21. Efficacy for reversal in ICH
Hemostatic Drug Therapies for Acute Spontaneous
Intracerebral Hemorrhage. Cochrane Database of
System Rev 2009.
Death 18.5% (rFVIIa) vs 19.4% (Placebo) RR 0.85
Death and/or Dependence 49.6% vs 51.7% RR 0.91
Essentially ineffective when looking at outcomes like
Mortality, which is all that really matters.

22. The ER coagulation
cascade
Tissue Damage
OTHER FACTORS
V, VIII, IX, XI, XII
1.FACTOR VIIa NOVO 7
2.FACTOR Xa ==FACTOR X
3.PROTHROMBIN== THROMBIN PRADAXA
FIBRONGEN ==FIBRIN CLOTS

23. FEIBA
 Activated Prothrombin Complex
Concentrates (II, VII, IX, and X)
 Dose 500U -1000U Often repeated for
sustained effect up to 2000Units
 Cost $1.59U/1000U = $1600/dose
 Typically 1-3 doses given

24. Safety
Cezary et al. Activated prothrombin complex concentrate
factor VIII inhibitor bypassing activity (FEIBA) for the
reversal of warfarin-induced coagulopathy. Int J Emerg
Med 2009.
Complications:
4/72 or 7% (1 peri-operative MI, 1 thrombosis of
CVC, 2 NSTEMI) VERY conservative.

25. FEIBA Efficacy
FEIBA used in warfarin reversal:
72 patients with life-threatening bleeds on coumadin.
54% Had INR < 1.4, vs 30% of patients who received
FFP.
No mortality benefit, reduced hematoma expansion
after ICH, rapid reversal of INR immediately (<15
minutes)

26. The ER coagulation
cascade
Tissue Damage
OTHER FACTORS
V, VIII, IX, XI, XII
1.FACTOR VIIa
FEIBA
2.FACTOR Xa ==FACTOR X
3.PROTHROMBIN== THROMBIN PRADAXA
FIBRONGEN ==FIBRIN CLOTS

27. Recommendations
 Evidence is poor
 Really endpoints like mortality are lacking
 No good RCT comparing these options
exist.
 Head bleeds are bad, GI bleeds are better,
and maybe reversing people doesn’t do
anything at all.

28. In light of good evidence
1. Pradaxa: check aPTT, if < 1.5normal = DONE
- FEIBA 500U
- rFVIIa 90mch/kg X 1 or about 1mg
- FFP and HEMODIALYSIS (if you can find someone to dialyze them)
- Activated Charcoal if within 2 hours of ingestion
2. Rivoroxaban:
- PCC’s 50U/kg Profilnine
- FEIBA 500-1000U
3. Warfarin
- FFP 15-20cc/kg minimum of 4U
- PCC’s > FFP for time to reversal (cost is similar)
- We have FEIBA (cost is more but rapidly reduces reversal time)

29. THANKS!!!