Reversal of Warfarin (Oral)

• Stop warfarin.
• Document INR, PT, APTT, FBC, U/Es, LFTs.
• Assess the source of bleeding (Clinically and radiologically).
• Correct haemodynamic compromise with IVF, RC transfusions to keep Hb≥70g/l.
• Use endoscopic and radiological measures.
• Reassess regularly.
• Investigate the causes of raised INR and, if restarting anticoagulation, consider a lower dose of warfarin or an alternative anticoagulant after discussion with senior clinician responsible for patient’s care.

Life threatening, major or critical haemorrhage:

Gastrointestinal haemorrhage (radiologically or clinically obvious), major intracranial bleed (CT or MRI documented), retroperitoneal bleed (CT or MRI documented), intra-ocular bleed (excludes conjunctival), spontaneous muscle haematoma associated with compartment syndrome, pericardial bleed, non-traumatic intra-articular bleed, requiring invasive procedure to stop bleeding, active bleeding from any orifice, plus: BP≤90mmHg systolic, or oliguria or ≥20g/l, or fall in haemoglobin.

Non-major haemorrhage:

Minor - any other haemorrhage that would not influence your decision to anticoagulate a patient.

No signs of haemorrhage:

INR 5-7.9 with low risk of high-risk haemorrhage, or INR≥8.

All patients, anticoagulation must be completely reversed (aiming for normal PT and APTT) in the presence of life-threatening haemorrhage or trauma:

• General haemostatic measures.
• Stop warfarin.
• Give Phytomenadione (vitamin K₁) IV 5mg undiluted injection slowly over 30 seconds in the emergency situations as per IV monograph (Medusa).
• Give intravenous prothrombin complex concentrate (PROTHROMPLEX TOTAL). Maximum dose is 5000units (200ml). Refer to PROTHROMPLEX TOTAL Accordion Section below - prior to administration.
• Recheck coagulation status after 20 – 30 minutes, at 4–6 hours, and at 24 hours (or earlier if clinically indicated). Further doses of Vitamin K₁ may be required in cases of extreme overdose. Maximum dose 40mg in 24 hours.
• In case of inadequate correction, consider other factors contributing to abnormal coagulation tests (see below) – seek advice from haematology.
• When haemostasis has been secured, consideration should be given as to whether anticoagulation should be restarted. Consider starting with prophylactic doses of LMWH initially, gradually increasing to therapeutic doses after discussion with senior clinician responsible for patient’s care, before switching to an oral anticoagulant.

In addition, head injury patients with strong suspicion of intracranial haemorrhage after a clear history of head injury should have their warfarin reversed with Prothromplex Total immediately and before CT and INR results are available.

• Stop warfarin for 1 – 2 days, until INR has fallen to therapeutic levels and bleeding has stopped.
• Administer vitamin K₁ 2mg orally.
• Re-assess at least twice daily until INR improving and bleeding stopped.
• Restart warfarin on a lower dose and investigate the causes of high INR.

Asymptomatic INR >5-7.9:

• Increased risk of haemorrhage: “high risk” patients whose risk of bleeding is approximately 15-fold higher. (older age, uncontrolled hypertension, diabetes, renal or liver failure, previous gastrointestinal or cerebral bleeds)
• Stop warfarin, monitor INR, and do not restart until INR <5.
• Consider hospital admission for monitoring.
• Consider giving vitamin K₁ 2mg orally.
  • Phytomenadione 2mg/0.2ml vials are licensed for oral administration
• Check INR the next day.
• Reduce warfarin dose. Investigate the causes of high INR.
• Low risk: Considered those patients who do not fit with above criteria:
• Stop warfarin, monitor INR and restart warfarin when INR <5.
• Reduce warfarin dose. Investigate the causes of high INR.

Asymptomatic INR ≥8:

• Increased risk of haemorrhage as noted above
• Give vitamin K 2mg orally & withhold warfarin.
  • Phytomenadione 2mg/0.2ml vials are licensed for oral administration
• Recheck INR at 24 hours. Ensure Senior/Consultant aware and reviewed.

Restart warfarin on a lower dose and investigate the causes of high INR after discussion with senior clinician responsible for patient’s care. If alternative anticoagulant considered this must be following discussion with senior clinician or with Haematologist (on-call if out of hours).

Causes of raised INR:

Common factors that can cause a high INR include:

• Taking more warfarin than prescribed.
• An acute illness or an illness altering warfarin metabolism like infection.
• Alcohol consumption greater than national guidelines.
• Starting new medications, for example antibiotic therapy, or stopping medications.
• Starting herbal products or over-the-counter medicines.
• Sometimes the cause of a high INR is unknown.

Inadequate coagulation correction:

Consider other causes:

• DIC.
• Lupus inhibitors.
• Inadequate replacement.
• Administration problems.
• Congenital deficiencies.

Warfarin:

Warfarin is a form of Vitamin K antagonist (VKA) anticoagulant. The mechanism of action is through inhibiting factors VII, IX, X, II, proteins C and S.

Onset of action is 2-5 days. Lab testing is through INR levels.

Other Vitamin K antagonists (VKA): Acenocoumarol and Phenindione not in use in UK.

Vitamin K1 (Phytomenadione):

Vitamin K1 is a cofactor for hepatic production of factors VII, IX, X, II.

Onset of action: 6-10 hours (oral) and 1-2 hours (IV).

Duration of action: 24-48 hours (oral and 12-14 hours (IV).

It is usually appropriate for intravenous Vitamin K 5 – 10 mg to be prescribed at the same time as Prothromplex Total to prevent a rebound rise in the INR once the effect of the Prothromplex Total has worn off.

Route

Oral route is preferred for patients with non-major bleeding. IV should be ordered only if patient has major bleeding or needs an emergent procedure (≤6 hours).

Avoid IM injections due to risk of development of haematoma and drug absorption is variable through IM injections.

Intravenous vitamin K1 may rarely cause anaphylaxis. Withheld it in patients with a history of previous severe allergic reaction to vitamin K.

Administration should be by slow IV bolus over at least 30 seconds (see references: Medusa NHS Injectable medications Guide and BNF).

PROTHROMPLEX TOTAL (prothrombin complex concentrate - PCC) is indicated if rapid correction of over-anticoagulation is required, such as in situations of major bleeding or when immediate emergency surgery is required.

PCC is a human blood product. It is not blood group specific. It contains factors, including VII, IX, X, II, factor X concentrate. Correction of haemostasis impairment could be achieved in 30 minutes and lasts for 6 -8 hours.

PCC contains heparin – contraindicated in patients with HIT and disseminated intravascular coagulation (DIC) due to high risk of thrombosis. Avoid in cases with known allergy to heparin and citrate.

Contact haematologist and discuss using alternative products like FFP.

PCC is relatively contraindicated in high-risk thrombosis like APLS and recent MI and thrombotic stroke (<1month).

In all clinical circumstances, an assessment of the likely risks and benefits of administration needs to be made. The need for PCC must be discussed with the patient’s consultant. 

PCC is prescribed in “international units” (specifically for units of factor IX per kilogram body weight). The dose should be calculated on an individual patient based on INR value, weight in Kilogram.

https://www.rarediseasehub.co.uk/medicines/bleeding-disorders/prothromplex-totalHub 2.0

Table 1 – PROTHROMPLEX TOTAL dose adjustment according to INR

• • Maximum dose is 5000units.
  • Reconstitute 500unit vial of PROTHROMPLEX TOTAL to 17ml using the sterile water and the reconstitution device supplied. Please refer to the instructions 6.6 in Summary of Product Characteristics (SmPC)    https://www.medicines.org.uk/emc/product/15237/smpc
  • Infuse immediately at an infusion rate not exceeding 2ml/minute (60 units/minute).
  • If allergic or anaphylactic-type reactions occur, the administration of PCC has to be stopped immediately.

Repeated treatment with human prothrombin complex is not usually required when vitamin K1 has been administered.

PCC dosing should be rounded to the nearest 500 international units (the transfusion laboratories generally stock 500 international unit and 1000 international unit vial sizes). PCC is prescribed in the patient’s drug Kardex and ordered from the transfusion laboratory by submitting a blood transfusion request form with patient details and calculated dose required. A reconstitution manual card is attached with PCC supply for guidance.

A helpful PCC dosing guide can be accessed in SmPC and reconstitution & administration methods.

PCC request does not require the authorisation of a haematologist.

Contact the duty haematologist if further advice is required.

FFP contains factors VII, IX, X, II (diluted), fibrinogen, proteins C and S.

Onset of action 1 -4 hours. Duration of action is ≤6 hours. Large volume administration is required to reverse high INR and only recommended if PCC is not available to use or patient allergic to PCC products including past history of Heparin induced thrombocytopenia (HIT). This will require haematologist approval unless it is ordered in the context of major haemorrhage protocol.