Anti-coagulation reversal

Warfarin

Warfarin is used in the management of venous or arterial thromboembolism.

Warfarin works by blocking the gamma-carboxylation of glutamic acid residues of the Vitamin K−dependent coagulation factors II, VII, IX and X.

This inhibition, results in decreased biological activity of factors II, VII, IX, X and protein C and protein S; which results in the prolongation of the international normalised ratio (INR).

Warfarin is associated with a risk of 1%-3% per year of significant haemorrhage leading to hospitalisation or death.

Recently, direct oral anticoagulants (DOAC) have been approved for the management of thromboembolic disease as an alternative to warfarin in certain patient populations.

Management of patients on warfarin undergoing invasive procedures

Interrupting warfarin therapy

When considering how to manage patients receiving warfarin who require surgery, the risk of thrombosis if warfarin is withheld needs to be balanced with the risk of bleeding if continued.

The Patient Blood Management (PBM) Guidelines: Module 2 – Perioperative provide some guidance with the following recommendation and practice point.

Recommendation 10:

In patients undergoing minor dental procedures, arthrocentesis, cataract surgery, upper gastrointestinal endoscopy without biopsy or colonoscopy without biopsy, warfarin may be continued (Grade B).

Practice point 10:

In patients receiving warfarin who are scheduled for elective non-cardiac surgery or other invasive procedures (excluding minor procedures—see Recommendation 10); specific management according to current guidelines is required (e.g. guidelines from the American College of Chest Physicians and the Thrombosis and Haemostasis Society of Australian and New Zealand (THANZ).

The THANZ guidelines provide a risk stratification strategy for the perioperative management of patients with a history of arterial and/or venous thromboembolism.

Key points from these guidelines include:

For minor procedures where bleeding risk is low, warfarin may not need to be interrupted.
Surgery can be conducted with minimal increased risk of bleeding if INR ≤ 1.5.
If necessary, warfarin can be withheld for 5 days before surgery, or intravenous vitamin K can be given the night before surgery.
Prothrombinex-VF use for warfarin reversal should be restricted to emergency settings.
Patients at high risk for arterial and venous thromboembolism should be discussed with a haematologist regarding the need for bridging anticoagulation.

Guidelines for the management of an elevated INR in adults

Management of patients on warfarin therapy with high INR in adults WITHOUT bleeding

INR greater than therapeutic range but <4.5

Warfarin	Reduce or omit the next dose*
Comments	Resume warfarin at reduced dose when INR reaches therapeutic range

INR 4.5–10.0 bleeding risk low

Warfarin	Stop
Measure INR	Within 24 hours
Comments	Resume warfarin at reduced dose when INR reaches therapeutic range

INR 4.5–10.0 bleeding risk high

Warfarin	Stop
Vitamin K	Give 1.0−2.0 mg oral or 0.5–1.0 mg intravenous
Measure INR	Within 24 hours
Comments	Resume warfarin at reduced dose when INR reaches therapeutic range

INR >10.0 bleeding risk low

Warfarin	Stop
Vitamin K	Give 3.0−5.0 mg oral or intravenous
Measure INR	Within 12 hours
Comments	Resume warfarin at reduced dose when INR reaches therapeutic range

INR >10.0 bleeding risk high

Warfarin	Stop
Vitamin K₁	Give 3.0−5.0 mg oral or intravenous
PTX-VF	15–30 IU/kg
Measure INR	Within 12 hours
Comments	Resume warfarin at reduced dose when INR reaches therapeutic range

Management of patients on warfarin therapy with high INR in adults WITH bleeding

INR ≥1.5 with life-threatening (critical organ) bleeding

Warfarin	Stop
Vitamin K	Give 5.0–10.0 mg intravenous
Prothrombinex-VF	Give 50 IU/kg
FFP	Give 150–300 mL If Prothrombinex-VF not available administer FFP 15 mL/kg
Measure INR	In 20 mins
Comments	Resume warfarin when bleeding ceased and adjust dose to maintain INR within therapeutic range

INR ≥2.0 with clinically significant bleeding (not life-threatening)

Warfarin	Stop
Vitamin K	Give 5.0–10.0 mg intravenous
Prothrombinex-VF	Give 30-50 IU/kg
FFP	If Prothrominex-VF not available administer FFP 15 mL/kg
Measure INR	In 20 mins
Comments	Resume warfarin when bleeding ceased and adjust dose to maintain INR within therapeutic range

INR <4.5 with minor bleeding with further bleeding risk low

Warfarin	Stop
Measure INR	Within 24 hours
Comments	Resume warfarin at reduced dose when INR reaches therapeutic range

INR <4.5 with minor bleeding with further bleeding risk high or INR>4.5 with minor bleeding

Warfarin	Stop
Vitamin K	Consider 1.0–2.0 mg oral or 0.5–1.0 mg intravenous
Measure INR	Within 24 hours
Comments	Resume warfarin at reduced dose when INR reaches therapeutic range

Notes: *Dose reduction may not be necessary if the INR is only minimally above therapeutic range (up to 10%); INR = International Normalised Ratio; FFP = fresh frozen plasma;

Management of an elevated INR caused by warfarin therapy

A supratherapeutic INR is a significant risk factor for bleeding.

General principles for preventing supratherapeutic INR involve careful monitoring and consideration of warfarin-drug interactions, including avoiding concomitant non-steroidal anti-inflammatory drugs, certain antibiotics and antiplatelet therapy except where clinical benefit is known e.g. mechanical heart valves, acute coronary syndrome or recent coronary stent insertion.

Management principles:

Withhold warfarin with careful monitoring
- Resume therapy at a lower warfarin dose when the INR approaches therapeutic range.
- If the INR is only minimally above the therapeutic range (up to 10%) dose reduction is generally not necessary.
Vitamin K
- Vitamin K is a safe and effective antidote to warfarin.
- Both oral and intravenous (IV) routes are effective in reducing a raised INR due to warfarin with a similar correction of INR by 24 hrs. IV has a more rapid response, within 6-8 hours.
- Anaphylaxis to IV vitamin K is rare.
- Vitamin K should not be administered by subcutaneous or intramuscular routes.
- Dosage of Vitamin K varies between 0.5 mg and 10 mg based on bleeding or risk of bleeding. See the Guidelines for the management of an elevated INR in adults for details.
Prothrombin complex concentrate (PCC) e.g. Prothrombinex-VF
- Prothrombinex-VF is a coagulation factor concentrate containing factors II, IX and X and a small amount of factor VII.
-  PCCs are reconstituted into a small volume for rapid infusion and have a fast onset of action.
- Prothrombinex-VF is able to completely reverse a supratherapeutic INR within 15 minutes however, vitamin K is also required to sustain the reversal effect as the half-lives of the infused clotting factors are similar to endogenous factors.
- The suggested dose of Prothrombinex-VF ranges from 15-50 IU/kg and is based on bleeding risk as outlined in the Guidelines for the management of an elevated INR in adults.
Fresh frozen plasma (FFP)
- Not routinely used to reverse warfarin anticoagulation.
- Where PCC is unavailable and emergency reversal is required, FFP should be used, along with Vitamin K to sustain the reversal effect.
- FFP is also used in addition to PCC in patients with major or life-threatening bleeding or INR > 10.0 accompanied by high risk of bleeding.

Life-threatening bleeding

For life-threatening (critical organ) and clinically significant bleeds, the consensus is to use the maximum dose of Prothrombinex-VF (50 IU/kg) with vitamin K (5-10 mg IV) and FFP (150-300 mL) or when Prothrombinex-VF is not available, use the maximum amount of FFP (15 mL/kg)(1). Refer to the Guidelines for the management of an elevated INR in adults and/or seek specialist haematology advice.