Strategies for Reversing Warfarin
Anticoagulation
W. Cederquist, MD, Anesthesiology PGY-V
Mentor: Paul Picton, MD
Case Discussion – Practical Updates in Anesthesiology 2014
Tues, February 4th, 2014
Disclosures
• No conflicts of interest to report
Case Presentation (1)
• HPI: 70 y.o. ASA 3 man presenting to ED with 12
hours of vomiting, loose stools and RLQ abdominal
pain.
• PMH: HTN and atrial fibrillation on warfarin
• VS: T 39°C; BP 108/63; HR 74 regular; RR 16;
SpO2 96% RA.
• Exam: 72 in, 100kg, BMI 30. Neurologic, HEENT,
cardiopulmonary, GU, MSK and skin wnl.
Tenderness at McBurney’s point, Rosving’s sign.
Case Presentation (2)
• Labs:
WBC 14.3 (4-10 K/mm3)
80% PMNs
Hct 46.8
(40-50 %)
Plt 173
(150-400 K/mm3)
COMP
Within normal limits
aPTT 31.6 (22.0-32.0 s)
PT 28.4
(9.8-12.5 s)
INR 2.8
Case Presentation (3)
• CT abdomen/pelvis with IV/PO contrast
• Surgical plan: Laparoscopic appendectomy
Case Presentation (4)
Surgery Note: “The patient will be transfused 3
units of FFP to correct his INR to less than 1.5.
The patient will have immediate INR check and
will be continued to be transfused with FFP
should he remain therapeutic... Once his INR
is reversed, the patient will be taken to the
operating room...”
Perioperative Course (1)
1349
1425
1624
1745
2040
2125
2136
2212
2230
0146
0200
0300
Arrival to ED
INR 2.8
CT abdomen/pelvis
Ciprofloxacin/Metronidazole Administered
1st FFP
2nd FFP
Arrived in Pre-Op Area
INR 2.2
3rd FFP and 4th FFP
INR 1.7
5th FFP
Facial edema and urticaria noted
Perioperative Course (2)
0412
0421
0431
0502
0545
0611
0845
0851
0858
0901
0942
1325
Patient In Room
Anesthesia Induction End
Urology Consult for Difficult Foley Placement
Surgical Incision
Converted to Open Ileocecetomy
INR 1.7
EBL 300cc
Surgical Dressing Complete
Extubated Awake
Transported to PACU
INR 1.8
Admitted to Surgical Ward
Perioperative Course (3)
• Post Op Course
- complicated by paroxysmal atrial fibrillation
• Outcome
- warfarin restarted at discharge to home on
postoperative day #4
Goals and Objectives
• Identify the hemostatic defect in warfarin
therapy
• Evaluate the safety and efficacy of three
methods to correct warfarin anticoagulation
• Critically appraise the association between an
elevated prothrombin time and bleeding risk
• Introduce prothrombin complex concentrate as
an alternative to FFP for warfarin reversal
Classical Coagulation Pathway
aPTT
PT/INR
Differential Diagnosis
Anticoagulants
warfarin, argatroban,
heparin
Liver disease
multiple etiologies
Vitamin K deficiency
malnutrition, antibiotic use
Factor deficiency
hemophilia, autoimmune
disease, coagulation
factor inhibitors
Warfarin
Factors
II
VII
IX
X
ACCP Guidelines 8th Edition (2008)
Coagulation Factor Activity vs INR
Gulati et al. Archives of Pathology & Laboratory Medicine ( 2011)
Classical Coagulation Pathway
Question
• What three general strategies are available
for the correction of warfarin-induced
coagulopathy?
- discontinue warfarin (days)
- supplement vitamin K (12 - 24 hours)
- replace clotting factors (immediate)
Vitamin K Supplementation
Phytonadione
ACCP Guidelines 8th Ed
Intravenous Vitamin K
- 178 patients on warfarin
- vitamin K 3 mg IV
- PT/PTT checked on day of procedure
Burbury et al. Br J Haematology (2011)
Intravenous Vitamin K
Normal Range
Burbury et al. Br J Haematology (2011)
Added to Chest Guidelines
Recommendations: “Anticoagulation reversal
for non-major bleeding should be with 1-3 mg
intravenous vitamin K (Grade 1B).”
Question
• What three general strategies are available
for the correction of warfarin-induced
coagulopathy?
- discontinue warfarin (days)
- supplement vitamin K (12 - 24 hours)
- replace clotting factors (immediate)
Replacement of clotting factors
Blood Product
(FFP)
Multiple factor replacement
(Prothrombin Complex
Concentrate)
Single factor replacement
(Recombinant Factor VIIa)
What’s in it?
Stanworth. Hematology (2007)
Professional Guidelines
• ASA Practice Guideline for Perioperative
Blood Transfusion (2006):
“FFP should be given … to achieve a minimum of
30% plasma factor concentration (usually
achieved with administration of 10-15 ml/kg
FFP), except for urgent reversal of warfarin
anticoagulation, for which 5-8 ml/kg FFP usually
will suffice.”
American Society of Anesthesiology. Anesthesiology (2006)
Making Assumptions
Surgery Note: “The patient will be transfused 3
units of FFP to correct his INR to less than
1.5…and will be continued to be transfused with
FFP should he remain therapeutic... ”
Assumptions:
1) FFP will decrease the bleeding risk
Will FFP decrease the bleeding risk?
- review of FFP
- multiple clinical endpoints
- evidence supporting FFP is weak
Stanworth. Hematology (2007)
Making Assumptions
Surgery Note: “The patient will be transfused 3
units of FFP to correct his INR to less than
1.5…and will be continued to be transfused with
FFP should he remain therapeutic... ”
Assumptions:
1) FFP will decrease the bleeding risk
2) FFP will correct the INR to < 1.5
Change in INR per unit FFP
Holland LL, Brooks JP. Am J Clin Path (2006)
Will FFP decrease the INR to 1.5?
Starting INR 1.5-1.8
Median INR change
= 0.07
Less than 1%
achieve
normalization of the
INR.
Abdel-Wahab et al. Transfusion (2006).
Where did that number come from?
Where did that number come from?
Holland LL, Brooks JP. Am J Clin Path (2006)
Replacement of clotting factors
Blood Product
(FFP, whole blood)
Multiple factor replacement
(Prothrombin Complex
Concentrate)
Single factor replacement
(Recombinant Factor VIIa)
Prothrombin Complex Concentrate
PCC
II
VII
IX
Hemophilia B
X
How is it made?
Ion exchange
chromatography
II
VII
IX
X
Adult dose: 25-50 U/kg
Pasteurize
Effect of PCC on clotting factors
Pabinger et al. J. Thromb Haemost (2008).
PCC vs FFP
PCC
FFP
Onset
immediate
limited by acquisition
time and infusion rate
Duration
~ 3-6 hours
~ 3-6 hours
Volume
↓↓↓
↑↑↑
Risks
thrombosis
allergic rxn, TRALI,
TACO, infection
Cost
+++
+
Added to Chest Guidelines
Recommendation: “For patients with warfarinassociated major bleeding, we suggest rapid
reversal of anticoagulation with four-factor
PCC rather than with plasma (Grade 2C).”
ACCP Guidelines 9th Edition (2012)
Coming soon to a pharmacy near you
PCC
II
IX
X
PCC
3 factor PCC
II
IX
X
3 factor PCC
Clinical Trials
- 202 patients taking warfarin
- equal in terms of “effective hemostasis”
- possibly fewer adverse events
Sarode et al. Circulation (2013)
New Oral Anticoagulants
- direct thrombin inhibitors (dabigatran)
- factor Xa inhibitors (-xabans)
- consider PCC if all else fails
Heidbuchel et al. Europace (2013)
Conclusions
• Identify the hemostatic defect in the
coagulopathic patient presenting for emergency
surgery.
• Use vitamin K for procedures that can be
delayed 12 hours, otherwise use FFP.
• Minor elevations in INR are unlikely to be
corrected by plasma transfusion.
• Prothrombin complex concentrate is a
promising alternative but further studies are
needed.