Management of Warfarin Reversal (in Adults)

• Peri-operative anticoagulation
• Management of Bleeding and of High INR in the absence of Bleeding
• Therapeutic Interventions
• Flowchart for the management of warfarin reversal

For guidance on the Indication Codes for the use of red cells, fresh frozen plasma, cryoprecipitate, platelets and prothrombin complex concentrate issued by the National Blood Transfusion Committee, supported by NICE NG24 2015, please see: Link

This guideline aims to give advice and support in the treatment of patients admitted for surgery or treatment who are taking warfarin for anticoagulation.

Peri-operative anticoagulation

For some invasive procedures, such as joint injections, cataracts and low risk endoscopic procedures (see BSG Guidelines) warfarin does not need to be stopped if the INR is in the therapeutic range.
As a general rule, warfarin should only be reversed for emergency surgery. For elective surgery, warfarin should be stopped to allow the INR to fall slowly back to normal prior to the procedure.

• Warfarin should not be taken for 5 days before surgery and, if possible, the INR should be determined the day before surgery to allow the administration of vitamin K if the INR is ≥1.5, so reducing the risk of cancellation. (See below)

Pre-operative bridging therapy (with treatment dose LMWH) should be considered if the thrombotic risk is especially high:

• Stroke/TIA/VTE within previous 3 months, (Please consider delaying surgery)
• VTE whilst on anticoagulation ever
• Target INR 3.5
• Metallic valve other than bileaflet aortic valve
• Previous stroke/TIA ever with 3 of following risk factors: CCF, HTN, >75yoa, Diabetes

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Management of Bleeding and of High INR in the absence of Bleeding

Major/life threatening bleeding
In terms of anticoagulation reversal, major bleeding can be defined as limb or life threatening bleeding that requires complete reversal immediately.

• 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 urgent clinical assessment of coagulation parameters.

• Patients on warfarin may be haemorrhagic for reasons other than the effect of the anticoagulant such as disseminated intravascular coagulation (DIC). An INR, full blood count, Prothrombin time (PT), Activated Partial Thromboplastin Time (APTT) and Clauss Fibrinogen should be determined (also Fibrin Degradation Products (FPD)/ D Dimer if DIC is a possibility)

• Patients on warfarin have reduced levels of factors II, VII, IX and X and rapid correction involves replacement of the preformed factors.

• Rapid correction is most effectively achieved by the administration of prothrombin complex concentrate (PCC)

• Stop warfarin and reverse anticoagulation with vitamin K and Prothrombin Complex Concentrates (PCC) (PCC may be contraindicated in the presence of DIC, discuss with haematologist is suspected) see dose below.

• Anticoagulation can be effectively reversed with PCC (dosed according to the INR: see table) and vitamin K 5mg (Phytonadione, Konakion MM® injection) by slow intravenous injection or intravenous infusion over 30 minutes.

• However, patients receiving warfarin may have an underlying hypercoagulable state and infusion of Prothrombin Complex Concentrate may exacerbate this

• In the absence of available concentrate licensed for this use, emergency treatment with 15 ml/kg of FFP and vitamin K 5 mg (Phytonadione, 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)

• In the event of life threatening bleeding, the same guidance applies for patients with mechanical heart valves i.e. full reversal of warfarin with PCC and vitamin K. In the event of bleeding that is non life threatening the individual balance of risks should be discussed with a consultant haematologist and/or a consultant cardiologist.

• Once PCC has been given, wait 20 minutes and perform another coagulation screen and assess the degree of correction of INR

• Seek further haematological advice if no 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

Non-major Bleeding

• Patients with non-major bleeding can be managed with vitamin K (Phytonadione) combined with temporary discontinuation of warfarin.

• Intravenous vitamin K (Phytonadione) produces a more rapid correction of the INR than oral vitamin K and should be used in preference in the bleeding patient.

• Significant correction of the INR is seen within 6–8 h after intravenous vitamin K use

• Patients bleeding at therapeutic levels of anticoagulation should be investigated for the source of bleeding.

INRs >5.0 and >8.0 in non-bleeding patients

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.

Table 1

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Therapeutic Interventions

Vitamin K (phytomenadione on eMeds)

• Vitamin K will reverse the action of warfarin partially or wholly depending on the route of administration and the dose used.
• Intravenous administration results in rapid correction of anticoagulation with significant effects on the INR at 4-6 hours
• The rate of reversal with oral vitamin K is slower and satisfactory reversal achieved by 24hrs. If the INR is still too high at 24h the dose of vitamin K can be repeated
• Only 500 micrograms is required to reduce the INR from > 5.0 to a target level of 2.0-3.0
• Vitamin K tablets are often poorly absorbed. The preferred formulation for administration of vitamin K orally is the intravenous preparation mixed in approximately 100ml of juice.
• Allergic reactions following intravenous administration are rare with new preparations of vitamin K.
• Subcutaneous absorption of vitamin K is erratic and not recommended
• Slow intravenous infusion doses should be diluted with 50ml of glucose 5%

e.g. Octaplex

• Octaplex is held in resus at LGI and in blood bank/transfusion laboratory at LGI and SJUH. 
• PCC is produced by the fractionation of pooled plasma from non-UK donors.
• PCC contains factors II, VII IX and X in approximately equal concentrations. It has undergone virucidal treatment during preparation (although some viral risk still remains) and does not need to be blood group specific.
• PCC is available in lyophilized powder form which is reconstituted in sterile water immediately prior to administration.
• Doses of between 25units/kg and 50units/kg have been used.
• Reversal of anticoagulation is rapid but due to the short half-life of Factor VII (6 hours), it is essential also to give intravenous vitamin K.
• Use of PCC has the potential to cause thrombosis and disseminated intravascular coagulation (DIC), particularly in patients with pro-thrombotic clinical conditions or liver disease. Almost all subjects treated with warfarin will, by definition, have a condition predisposing to thrombosis and so risks versus benefits must be assessed on an individual patient basis.
• The table shown below is a guide to the dosing of Octaplex when reconstituted according to the manufacturer’s instructions.  500 units of Octaplex (expressed as international units of factor IX activity) is reconstituted in 20ml of water for injection. Note that no more than 3,000 units (120ml) should be administered as a single dose.

*Prescribe as “units” on paper blood transfusion or factor concentrate chart
*The single dose should not exceed 3000units (120 mL Octaplex).
*The dose should be rounded up to the nearest multiple of 500 units (20 ml vial)
Table 2

Administration of Prothrombin Complex Concentrate (PCC)

• The PCC used in LTHT is Octaplex which is a concentrate of coagulation factors II, VII, IX and X and is available via the Transfusion Laboratory at the LGI and SJUH.
• For prompt reversal of warfarin anticoagulation dosing according to the table above is recommended.
• The product must be reconstituted from a dried powder using a supplied diluent aseptically and used immediately.
• Octaplex should be given by slow IV infusion with a syringe pump, starting at a rate of 1 ml/minute (60ml/hour) for 5 minutes, increasing to a maximum of 2-3 ml/minute (120-180ml/hour) as tolerated. In an emergency life-threatening situation, use a rate of 4 to 8ml/minute.
• There is a small risk of an allergic reaction - if this occurs, then the infusion should be stopped immediately and standard allergy/anaphylaxis therapy should be initiated. As a precautionary measure, patients pulse rate should be measured before and during the infusion. If a marked increase in the pulse rate occurs, the infusion speed must be reduced or the administration must be interrupted.
• Do not use Octaplex or PCC in any situation other than warfarin reversal without first consulting a haematologist.
• Further information on dosage etc. can be found in the Octaplex information leaflet which accompanies the product
• 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
• Check the INR and coagulation screen 15-20 minutes after completion of infusion of Octaplex.
• Use a clean venepuncture from the opposite arm. 
• Always check the INR again after 24 hours or before if incomplete correction of the INR has occurred or if the patient continues to bleed.
• Remember that there will always be a rebound of the INR if vitamin K is not administered or is administered in an insufficient dose.
• Note that Octaplex contains heparin and is therefore contraindicated in patients with a history of heparin induced thrombocytopenia

Fresh Frozen Plasma (FFP)

In major or life-threatening bleeding, the deficient clotting factors II, VII, IX and X should be replaced as quickly as possible. Previously, FFP has been used for this purpose, at a recommended dose of 15ml/kg. There are a number of reasons why FFP is not the optimal form of clotting factor replacement:

• FFP contains insufficient amounts of factors II, VII, IX and X to achieve physiological correction of anticoagulation. After infusion of 15ml/kg of FFP, clotting factor levels typically remain below 20% and there is evidence that FFP is less effective than PCC in achieving adequate warfarin reversal in patients with major bleeding.
• The recommended volume for a 70kg patient is 1050ml (approximately 4 units) which may be a problem if there is pre-existing cardiovascular impairment.
• FFP has to be blood group specific so the patient’s blood group must be known.
• Thawing may incur a delay in administration
• FFP is a single donor product that has not been subjected to a virus-inactivation procedure and therefore carries a small but definite risk of transmission of blood-borne pathogens.
• There is a risk of TRALI* and other allergic/anaphylactic reactions with the administration of FFP

Therefore, FFP should only be used for reversal of over-anticoagulation when Prothrombin Complex Concentrate is not available or contraindicated.

*TRALI: Transfusion related acute lung injury; acute dyspnoea with hypoxia and bilateral pulmonary infiltrates during or within 6 hours of transfusion, not due to circulatory overload or other likely causes

Rapid reversal necessary (urgent surgical procedure)
Urgent means clinically essential, not administratively convenient, to perform immediate surgery.
For reversal in 4 to 24 hours:

• Vitamin K 2-5mg (Konakion MM® injection) used orally or by slow intravenous injection (Konakion MM® injection) 5mg recommended for patients with a hip fracture requiring urgent surgery
  For reversal within 1 hour:

• Prothrombin Complex Concentrate (Octaplex, dosed as per Table above)

Do not use FFP for reversal unless Prothrombin Complex Concentrate (PCC) is not available. Always consult a Haematologist

Administration of prothrombin complex concentrate (PCC)

• The PCC used in LTHT is Octaplex which is a concentrate of coagulation factors II, VII, IX and X and is available via the Transfusion Laboratory at the LGI and SJUH.
• For prompt reversal of warfarin anticoagulation dosing according to the Table above is  recommended
• The product must be reconstituted from a dried powder using a supplied diluent under aseptic conditions and used immediately. It should be administered as an IV slow bolus initially at 1 ml/minute and not faster than 2-3ml per minute.
• Do not use Octaplex or PCC in any situation other than warfarin reversal without first consulting a haematologist.
• Further information on dosage etc. can be found in the Octaplex information leaflet which accompanies the product
• 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
• Check the INR and coagulation screen 15-20 minutes after completion of infusion of Octaplex.
• Use a clean venepuncture from the opposite arm. 
• Always check the INR again after 24 hours or before if incomplete correction of the INR has occurred or if the patient continues to bleed.
• Remember that there will always be a rebound of the INR if vitamin K is not administered or is administered in an insufficient dose.
• Note that Octaplex contains heparin and is therefore contraindicated in patients with a history of heparin induced thrombocytopenia.

Reintroduction of oral anticoagulants

• Timing of reintroduction of oral anticoagulants will depend on the risk of recurrent/post-operative haemorrhage.
• The 5-7 day delay for achievement of anticoagulation with oral vitamin K antagonists will also influence this decision
• The dose of vitamin K if over 2mg may affect the response to warfarin for a number of days and should be taken into account when re-initiating if the INR is not increasing.

.Head injury in patients on warfarin

• Measure the INR in all patients on warfarin with head injury 
• Have a low threshold for performing a CT scan in the warfarinised patient with a head injury 
• Reverse warfarin in patients with a head injury if 
• There is strong clinical suspicion of intracranial bleeding (before INR and CT results are available). Use PCC and intravenous vitamin K.
• There is evidence of intracranial bleeding on a CT scan. Use PCC and IV vitamin K
• The patient has a supratherapeutic INR and a normal CT. Use oral vitamin K, and confirm that the INR has been reduced to at least 2.0. Monitor the INR carefully for 4 weeks as delayed bleeding may occur. Keep the INR close to 2.0 for 4 weeks.  

Description of a target INR
The international normalised ratio (INR) is a recommended method for reporting prothrombin time results for control of oral anticoagulation. Since adoption of the INR system it has been usual practice to adjust the dose of warfarin, or other oral vitamin K antagonist, to maintain the INR within a therapeutic range.

The INR should not be used as a routine measure of coagulation in areas other than warfarin therapy; e.g. the prothrombin time is the primary measurement in assessing the severity of paracetamol overdose.

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Flowchart for the management of warfarin reversal

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