Strategies for Reversing Warfarin Anticoagulation

W. Cederquist, MD, Anesthesiology PGY-VMentor: Paul Picton, MD

Case Discussion – Practical Updates in Anesthesiology 2014Tues, 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 Arrival to ED1425 INR 2.81624 CT abdomen/pelvis1745 Ciprofloxacin/Metronidazole Administered2040 1st FFP2125 2nd FFP2136 Arrived in Pre-Op Area2212 INR 2.22230 3rd FFP and 4th FFP0146 INR 1.70200 5th FFP0300 Facial edema and urticaria noted

Perioperative Course (2)

0412 Patient In Room0421 Anesthesia Induction End 0431 Urology Consult for Difficult Foley Placement0502 Surgical Incision0545 Converted to Open Ileocecetomy0611 INR 1.70845 EBL 300cc0851 Surgical Dressing Complete0858 Extubated Awake0901 Transported to PACU0942 INR 1.81325 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

PT/INRaPTT

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

ACCP Guidelines 8th Edition (2008)

Factors

II

VII

IX

X

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)

ACCP Guidelines 8th Ed

Vitamin K Supplementation

Phytonadione

Intravenous Vitamin K

Burbury et al. Br J Haematology (2011)

- 178 patients on warfarin- vitamin K 3 mg IV- PT/PTT checked on day of procedure

Intravenous Vitamin K

Burbury et al. Br J Haematology (2011)

Normal Range

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

Assumptions: 1) FFP will decrease the bleeding risk

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... ”

Will FFP decrease the bleeding risk?

- review of FFP

- multiple clinical endpoints

- evidence supporting FFP is weak

Stanworth. Hematology (2007)

Making Assumptions

Assumptions: 1) FFP will decrease the bleeding risk2) FFP will correct the INR to < 1.5

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... ”

Change in INR per unit FFP

Holland LL, Brooks JP. Am J Clin Path (2006)

Will FFP decrease the INR to 1.5?

Abdel-Wahab et al. Transfusion (2006).

Starting INR 1.5-1.8

Median INR change = 0.07

Less than 1% achieve normalization of the INR.

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

Hemophilia B

II

VII

IX

X

PCC

How is it made?

Ion exchange chromatography

Pasteurize II

VII

IX

X

Adult dose: 25-50 U/kg

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 warfarin-associated 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

II

IX

X

PCC

3 factor PCC II

IX

X

PCC

3 factor PCC

Clinical Trials

Sarode et al. Circulation (2013)

- 202 patients taking warfarin

- equal in terms of “effective hemostasis”

- possibly fewer adverse events

New Oral Anticoagulants

Heidbuchel et al. Europace (2013)

- direct thrombin inhibitors (dabigatran)

- factor Xa inhibitors (-xabans)

- consider PCC if all else fails

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.