Guidelines for the management of warfarin reversal

This provides a protocol for best clinical practice when managing warfarin reversal therapy. It applies to
adult in-patients who need warfarin reversal to lower their INR, or who are on warfarin and bleeding, or
who are on warfarin and require immediate surgery.
Refer to flowchart for summary p5.

1. The Bleeding Patient

Bleeding while on oral anticoagulants increases significantly with INR levels >5.0. Therapeutic decisions
are dependent on the INR and whether there is minor or major bleeding. The dose of vitamin K used to
reverse over-anticoagulation depends on the INR.

Recommendations for management are given in Table 1 overleaf:

1.1. Major/life threatening bleeding

• This relates to patients with intracranial or rapid onset neurological signs, intra-ocular
(not conjunctival) bleeds, compartment syndrome, pericardial bleeds or those with
active bleeding and shock. These patients need an urgent clotting screen
• Patients on warfarin may be bleeding for other reasons than the effect of the
anticoagulant such as disseminated intravascular coagulation (DIC). A full blood
count, INR, APTT and Fibrinogen should be determined (also D-Dimers if DIC is a
possibility)
• Contact a haematologist at this stage
• Stop warfarin and reverse anticoagulation with Vitamin K and Prothrombin Complex
Concentrate (PCC), or FFP if PCC not available (PCC may be contraindicated in
the presence of DIC, discuss with haematologist)
• Anticoagulation can be effectively reversed with 30 units/kg PCC and Vitamin K 5mg
(Konakion MM injection) by slow intravenous injection
• However, patients receiving warfarin may have an underlying hypercoagulable state,
and infusion of PCC may exacerbate this - discuss with haematologist
• In the absence of available concentrate licensed for this use, emergency treatment
with 15ml/kg of FFP and Vitamin K 5mg (Konakion MM injection) by slow intravenous
injection will partially reverse anticoagulation, though the levels of individual factors
will typically remain <20% and larger doses should be given if possible (recommend
30ml/kg)
• For patients with prosthetic heart valves, full reversal of oral anticoagulants with
Vitamin K may result in prolonged oral anticoagulant resistance and the possibility of
valve thrombosis and thromboemboli
• Once the PCC has been given, wait 20 minutes and perform another clotting screen
and assess the degree of correction of INR
• Seek further advice if no further improvement takes place
• The degree of reversal must be decided on an individual basis. All patients with
bleeding should be evaluated to identify if there is a local anatomical reason for
bleeding

1.2. Significant bleeding without haemodynamic compromise

Stop warfarin

Give Vitamin K 2mg (Konakion MM injection) by slow intravenous injection

Consider using PCC 30 units/kg - discuss with haematologist

Recheck clotting screen at 4 hours or sooner if there is clinical deterioration
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Authors: Helen Maria, Transfusion Practitioner & Dr. Sarah Wexler, Consultant Haematologist
Date written: December 2006
For review: December 2008

Retest if necessary and seek haematological advice

Bleeding may occur when patients are not over-anticoagulated. In these circumstances it may still be
necessary to reverse anticoagulation and identify the cause of bleeding.

1.3. Minor bleeding

Relevant to patients with INR >8.0, no bleeding or minor bleeding

• Stop warfarin
• If no other risk factors for haemorrhage, stop treatment until INR <5.0
• If risk factors for haemorrhage or minor bleeding (e.g. age >70 years, previous
bleeding complications, epistaxis) consider giving Vitamin K 2mg Oral (Konakion MM
injection used orally) or 1mg slow intravenous injection (Konakion MM injection)
• Recheck clotting at 24 hours or sooner if there is clinical deterioration

2. INR too high but not bleeding

2.1. INR >3.0 and <6.0 (target INR of 2.5)
INR >4.0 and <6.0 (target INR of 3.5)

• Stop warfarin, reassess regularly

• Restart warfarin when INR <5.0

2.2. INR >6.0 and <8.0

• Stop warfarin, reassess regularly

• Restart warfarin when INR <5.0

Table 1

INR range/presence of bleeding? Action required

INR >3.0 and <6.0 (target INR 2.5)
1: Stop warfarin
INR >4.0 and <6.0 (target INR 3.5)
2: Restart warfarin when INR <5.0
No bleeding
INR >6.0 and <8.0 1: Stop warfarin
NO bleeding or minor bleeding 2: Restart when INR <5.0
1: Stop warfarin
INR >8.0 2: Restart warfarin when INR <5.0
No bleeding or minor bleeding 3: If other risk factors for bleeding, give 0.5-2.5mg oral
Vitamin K
1: Stop warfarin
2: Give Prothrombin Complex Concentrate 30units/kg or
Major bleeding
FFP 15ml/kg (if PCC not available)
3: Give 5mg Vitamin K (oral or IV)

NB: Fresh Frozen Plasma (FFP) has only a partial effect, is not the optimal treatment, and should
never be used for the reversal of warfarin anticoagulation in the absence of severe bleeding. It has
been shown that FFP does not contain sufficient concentration of the Vitamin K factors
(especially Factor IX) to reverse the bleeding deficiency (although it will reduce the INR).
Both FFP and Prothrombin Complex Concentrate (PCC) are plasma products and therefore carry
the risk of transfusion transmitted infection and other transfusion related complications. It is
important they are used appropriately and their prescription and rationale for use are recorded in
the patient’s notes.
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Authors: Helen Maria, Transfusion Practitioner & Dr. Sarah Wexler, Consultant Haematologist
Date written: December 2006
For review: December 2008
3. Rapid reversal of warfarin prior to urgent surgical procedure
Urgent means clinically essential, not administratively convenient, to do immediate surgery.

For reversal in 4 to 24 hours:

• Vitamin K 2mg Oral (Konakion MM injection used orally) or 1mg slow intravenous
injection (Konakion MM injection)

For reversal within 1 hour:

• Prothrombin Complex Concentrate (PCC) 30 units/kg using a slow IV bolus over 10-
15 minutes

Do not use FFP for rapid reversal unless PCC is not available. Always consult a Haematologist.

4. Reintroduction of oral anticoagulants

• Timing of reintroduction of oral anticoagulants will depend on the risk of post-

operative haemorrhage – generally warfarin can be restarted once haemostasis is
achieved
• Warfarin will take 48-72 hours to reach full effect – this could influence the decision
when to restart
• In many instances oral anticoagulants can be started again as soon as the patient
has an oral intake

5. References
BCSH ‘Guidelines on oral anticoagulation’, British Journal of Haematology, 1998, 101, 374-387

BCSH ‘Guidelines for the use of fresh frozen plasma, cryoprecipitate and cryosupernatant’, British Journal
of Haematology, 2004, 126, 11-28

‘Management of warfarin reversal’, Leeds Teaching Hospitals NHS Trust August 2004

‘Warfarin reversal’, Hanley, J.P. Journal of Clinical Pathology 2004;57;1132-1139

‘Beriplex P/N reverses severe warfarin induced overanticoagulation immediately and completely in
patients presenting with major bleeding.’ Evans G., Luddington R., Baglin T; British Journal of
Haematology, 2001;115;998-1001

6. Appendix

Administration of Prothrombin Complex Concentrate (PCC)

•
® ®
The brands of PCC used in the RUH are Octaplex and Beriplex . They contain a
concentrate of human coagulation factors II, VII, IX and X and are available via the
Blood Bank laboratory x4735 bleep 7555
• PCCs can only be used after authorisation by a haematologist
• For prompt reversal of warfarin anticoagulation in the presence of haemorrhage due
to over-warfarinisation, a dose of 30 units/kg is recommended
• The product must be reconstituted from a dried powder using a supplied diluent in
aseptic conditions over not more than 10 minutes. It should then be administered as
an IV slow bolus over 10-15 minutes

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Authors: Helen Maria, Transfusion Practitioner & Dr. Sarah Wexler, Consultant Haematologist
Date written: December 2006
For review: December 2008
 • Refer to monograph in IV drugs folder
• Regular monitoring of the coagulation status is indicated during the treatment as the
use of high doses of PCC has been associated with instances of myocardial
infarction, DIC, venous thrombosis and pulmonary embolism
• The on-call Haematologist can be contacted via switchboard
•
®
Octaplex costs £210 for a vial containing 500u (currently £0.42 per unit) and is
licensed
•
®
Beriplex costs £175 for a vial containing 500u (currently £0.35 per unit) and is
unlicensed

Vitamin K (phytomenadione)

• Oral vitamin K is almost completely absorbed, making it as effective as intravenous

vitamin K with the delay in action hardly influenced by the absorption time
• Only 500 micrograms is required to reduce the INR from >5.0 to a target level of 2.0
– 3.0
• Vitamin K tablets contain 10 mg phytomenadione which will completely reverse
anticoagulation. Therefore, when partial correction is required is may be necessary to
give intravenous vitamin K or alternatively give the intravenous preparation orally
• Allergic reactions following intravenous administration are rare with new preparations
of vitamin K. If the INR is still too high at 24 hours the dose of vitamin K can be
repeated
• Subcutaneous absorption of vitamin K is erratic and not recommended

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Authors: Helen Maria, Transfusion Practitioner & Dr. Sarah Wexler, Consultant Haematologist
Date written: December 2006
For review: December 2008
 Flowchart for the management of warfarin reversal
See guidelines for full details

The bleeding patient INR too high, but not bleeding

Major/life threatening bleeding INR >3.0 and <6.0 (target INR of 2.5)
INR >4.0 and <6.0 (target INR of 3.5)
•Intracranial
•Intraocular •Reduce warfarin dose or stop
•Compartment syndrome •Restart warfarin when INR <5.0
•Pericardial
•Active bleeding and shock INR >6.0 and <8.0
Urgent clinical assessment •Stop warfarin
Check clotting screen
•Restart warfarin when INR <5.0
Contact Haematologist

•Stop warfarin
•Vitamin K 5mg (Konakion MM injection) by
slow IV injection
•PCC 30 units/kg
The warfarin patient and
Check clotting screen 20 minutes post surgery
administration
•Adequate correction – recheck in 4 hours
•Inadequate correction – consider other causes, •Elective surgery – always plan in advance
seek haematologist advice •Decide on a ‘safe’ INR for the procedure
•If surgery is postponed, reassess coagulation

Significant bleeding without

Full warfarin reversal
haemodynamic compromise
•Stop warfarin 6 days pre-op
•Stop warfarin •Check INR on admission or morning of
•Vitamin K 5mg (Konakion MM injection) operation
by slow IV injection
•Consider PCC 30 units/kg IV Rapid reversal necessary
•Check clotting screen at 4 hours or sooner if clinical
deterioration (urgent surgical procedure)

Reversal in 4 to 24 hours
Minor bleeding •Vitamin K 2mg Oral (Konakion MM injection
used orally) or 1mg slow IV injection
•Stop warfarin (Konakion MM injection)
•Consider Vitamin K 2mg Oral (Konakion MM injection
used orally) or 1mg by slow IV injection Reversal within 1 hour
•Check clotting screen at 24 hours or sooner if •PCC 30 units/kg
clinical deterioration •Contact Haematologist

Note:
•Use of Prothrombin Complex Concentrate (PCC) can only authorised by a Haematologist – contact via switchboard
•PCC may induce a prothrombotic state. Use with caution in patients with DIC or decompensated liver disease. See product insert for more
information about dosage, administration or contraindications.
•To give PCC use a slow IV bolus. Obtain via the Transfusion Laboratory on x4734/4735 or bleep 7555 out of hours.
•In serious but non-life threatening bleeding (e.g. GI bleeding or epistaxis without haemodynamic compromise) prompt reversal with IV
Vitamin K is indicated
•Vitamin K (phytomenadione) may rarely cause anaphylaxis. Give by slow IV bolus.
•Oral vitamin K: use the Trust preparation of IV Konakion® (Roche) given orally. Alternatively the Konakion paediatric formulation may be
used.
For more information please refer to the accompanying RUH guidelines or the BCSH guideline on anticoagulation. Contact the Transfusion
Laboratory on x4734/4735 with any queries.

5
Authors: Helen Maria, Transfusion Practitioner & Dr. Sarah Wexler, Consultant Haematologist
Date written: December 2006
For review: December 2008