While the effects of Warfarin can be reversed, some of the newer oral anticoagulants do not have direct antidotes; therefore, management should focus on resuscitation and factor replacement. ¹³ Early haematological advice from the MTS’s is recommended to guide management.

Vitamin K

Vitamin K, given orally or intravenously (Phytomenadione), can be used to accelerate Warfarin reversal by counteracting its effects on Vitamin K-dependent coagulation factor synthesis. ⁶ The intravenous route achieves a more rapid response compared with oral administration, with an onset of action seen within 6-8 hours. ¹ Its effect is not immediate but will progress over time as the liver synthesizes sufficient quantities of coagulation proteins (factors II, VII, IX, X) dependent on Vitamin K. The usual dose is 5-10mg IV given as a bolus dose.

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Transfusion support

Fresh Frozen Plasma (FFP)

Replacement is required to correct the low levels of factors II, VII, IX, and X induced by warfarin. FFP contains all coagulation factors present in whole blood, but it is not a factor concentrate; therefore, multiple units may be required. The use of plasma requires the treating facility to have appropriate facilities for frozen plasma storage and thawing. The patients’ blood group must be determined (or group AB plasma may be used), and the time taken for infusion are all factors to be considered. ¹

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Anti-fibrinolytic agents

Tranexamic Acid (TXA)

Consideration of the use of the anti-fibrinolytic agent TXA IV 15-30mg/kg, followed by a continuous infusion at 1mg/kg/hr until bleeding is under control in Factor Xa inhibitors. There is limited evidence of the clinical benefit for TXA in this setting, and treatment should not delay resuscitative efforts. ¹⁴

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Pro-haemostatic agents

Prothrombin Complex Concentrates (PCC’s)

Prothrombinex-VF is the only PCC product currently available for use in Australia and NZ for warfarin reversal. It is a three-factor PCC (II, IX, and X) with low levels of factor VII. Prothrombinex-VF can be rapidly reconstituted into a small volume for infusion over a few minutes with a fast onset of action. The early use of PCC is recommended for the emergency reversal of Vitamin K-dependent oral anticoagulants (Warfarin). Prothrombinex-VF is able to completely reverse an elevated INR within 15 minutes, but due to the short half-life, it should be supplemented with Vitamin K to sustain the effect. ¹ In patients with life-threatening bleeding, supplementing factor VII by administering FFP should ensure optimal reversal of the anticoagulant effect of warfarin. Reversal of Direct Factor Xa inhibitors (Rivaroxaban, Apixaban) cannot be achieved with PCC; however, small doses of PCC will optimize coagulation in the presence of vitamin K deficiency or unknown co-administration of vitamin K antagonists and may act as a partial bypassing agent in very high doses and can be considered in extreme cases. PCC is not suggested for use in patients being treated with direct thrombin inhibitors (Dabigatran). ¹⁵ A specific reversal agent, Idarucizumab, is available in some centers for the reversal of Dabigatran (see below). The use of PCC does carry the increased risk of venous and arterial thrombosis during the recovery period; therefore, careful consideration of its use should be weighed against the need for rapid correction of coagulopathy.

Recombinant Factor VIIa – rFVIIa (Novoseven)

rFVIIa is a novel agent used to control intractable hemorrhage. rFVIIa promotes the formation of clots by activating the extrinsic clotting cascade, which leads to thrombin converting fibrinogen to fibrin. Ideally, the following should be present before rFVIIa administration:

• Haematocrit >24%
• pH >7.2
• Platelets >50 x 10E9/L
• Fibrinogen >1.0g/L

An IV Bolus of 50mcg/kg may be trialed if critical bleeding from Factor Xa inhibitors. Each hospital setting will have its own local procedure for the use of Novoseven in the management of life-threatening bleeding.

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Reversal agents

Idarucizumab

Idarucizumab is a monoclonal antibody fragment that binds free and thrombin-bound dabigatran and neutralizes its activity, resulting in the complete reversal of the anticoagulant effect. Its effect is immediate and lasts for 24 hours. ¹⁶ The complete dose of 5g should be given as two consecutive IV infusions over 5-10 minutes each. As it is a fairly new drug on the scene, its availability is limited, and in Victoria, it is only located at The Alfred and Royal Melbourne Major Trauma Centres.