Managing an excessively prolonged INR or bleeding caused by warfarin therapy
Warfarin is used for preventing and treating venous or arterial thrombosis and embolism. It is a potentially hazardous drug, causing major bleeding in 1-2% of people treated, including intracranial bleeding in about 0.1- 0.5% during each year of therapy. Warfarin acts by blocking the gamma-carboxylation of glutamic acid residues of vitamin K dependent coagulation factors, resulting in decreased biological activity of factors II, VII, IX and X and the natural anticoagulants Protein C and S. The management of excessive anticoagulation due to warfarin largely depends on whether or not the patient is bleeding, the extent and site of bleeding, the indication for anticoagulation, and the degree of suppression of these vitamin K dependent factors.
An INR above 5.0 requires close monitoring and often needs intervention, as determined by the level of the INR and the presence or absence of bleeding. Risk factors include old age, serious illness (cerebral, cardiac, kidney or liver disease), cerebrovascular disease, peripheral vascular disease, and an unstable anticoagulant effect. Non-steroidal anti-inflammatory drugs and alcohol abuse may also contribute.
Managing an excessively prolonged INR or bleeding caused by warfarin therapy may include:
- Withholding warfarin.
- Vitamin K1 (phytomenadione) – it takes approximately 8-12 hours for the effects of Vitamin K1 to become apparent. Large doses (eg 10-20 mg) may produce some resistance to re-warfarinisation, but there is less resistance to smaller doses (eg 1-5 mg) which are still effective in correcting an abnormally high INR within 24 hours in most cases. Larger doses are appropriate if a clinical decision has been made to discontinue further treatment with warfarin.
- Plasma transfusion – usually requires 10-15 mL/kg to correct the coagulopathy; however, the potential dangers of volume overload and allergic reactions must be considered. The effect is immediate.
- Prothrombinex-VF – the advantages of Prothrombinex-VF over FFP include the small volume required, the fact that a full dose can be administered in minutes, and there is no time delay due to the need to thaw product or blood group the patient. It is important to note however, that the use of Prothrombinex-VF has been associated with an increased incidence of thromboembolism and Prothrombinex-VF contains only small amounts of Factor VII.
Consensus guidelines for warfarin therapy have been prepared by the Australasian Society of Thrombosis and Haemostasis. Their position statement in relation to managing overdose and bleeding during warfarin therapy is shown in the table below.
|
| Clinical Setting | Action |
INR >5.0 but <9.0 (no bleeding)
| Stop warfarin, give 1-2.5 mg vitamin K1, measure INR in 6-12 hours, restart warfarin at reduced dose once INR is <5. |
| INR >9.0 (no bleeding) | Stop warfarin, give 5 mg vitamin K1, measure INR in 6-12 hours, restart warfarin at reduced dose once INR is <5. Clotting factor replacement† if high risk of bleeding. |
Major bleeding (any level of INR)
| Stop warfarin, give 5 mg vitamin K1, clotting factor replacement,
measure INR as required, assess need to restart warfarin. |
INR – International Normalised Ratio.
†Blood products available in Australia for clotting factor replacement after warfarin overdose include fresh frozen plasma and Prothrombinex-VF.
*Based on Makris et al, 199618 |
Interrupting warfarin therapy for elective surgery
When there is a need for surgery, the risk of perioperative bleeding under continued warfarin therapy must be balanced against the risk of thromboembolism if warfarin therapy is stopped. Many surgical procedures, dependent on the site of surgery, can proceed under continued warfarin cover without undue bleeding provided the INR during and soon after surgery is about 1.5-2.0. The effect of warfarin must be completely reversed for procedures where even minor bleeding might cause critical damage (as in neurosurgery, plastic surgery and regional anaesthesia).
Gallus et al state that "the absolute daily risk of a serious thromboembolic event is small in most people with atrial fibrillation, previous systemic embolism or a prosthetic heart valve. Thus it is safe to stop warfarin therapy for several days before and after surgery in such patients. High-dose therapeutic heparin cover for these indications is rarely indicated as the risk of bleeding is usually prohibitive. The risk of recurrence is greatest during the first four weeks after venous thromboembolism, so warfarin therapy should not be interrupted during this time if at all possible"(17). However this position is not universally accepted.
Interrupting warfarin therapy in the emergency setting
Immediate reversal of warfarin is required when there is major bleeding, including:
- Emergency surgery
- Life-threatening or limb-threatening bleeding
- Intracranial or spinal haemorrhage
- Significant gastrointestinal haemorrhage (haematemesis and melaena)
In these circumstances it is recommended that there is consultation with a haematologist. For patients with prosthetic heart valves, the degree of anticoagulant reversal should be discussed with the cardiologist.
The following management approach is recommended in the emergency setting:
- Stop warfarin
- Reversal with 1 – 5 mg of vitamin K1 (slow IV or oral) should be individualised
- Give Prothrombinex-VF: 25 -50 IU/kg and a small dose of FFP* dependent on the clinical circumstance and level of the INR.
OR
- Full replacement with FFP 10 – 15mL/kg
Note: *300mL of FFP (to supply factor VII). Prothrombinex-VF is contraindicated in patients with clinical/laboratory signs of thrombosis or DIC.
Re-introduction of anticoagulant needs to be individualised and take into account the risks of bleeding and thrombosis.