Reversal of Antithrombotic Therapies
Reversal of anticoagulant therapy may be necessary when a patient is found to be over-anticoagulated, develops bleeding problems or requires an invasive procedure. The general principles are similar in each situation and all cases require an individualised risk:benefit assessment. The peri-operative anticoagulant management of patients receiving warfarin is covered in detail here.
Patients with major or life-threatening bleeding, irrespective of their indication for anticoagulation (even patients with prosthetic metal heart valves) will usually require complete reversal of their anticoagulant therapy, at least temporarily.
Patients with minor bleeding, or over-anticoagulated without bleeding, will usually require temporary cessation of anticoagulant therapy (+/- small doses of reversing agents) to achieve a low-therapeutic level of anticoagulation.
General management and drug therapy
Intravenous unfractionated heparin
Subcutaneous low molecular weight heparin (LMWH)
- Stop LMWH. Most LMWHs have an elimination half-life of around 2 – 4 hours following subcutaneous injection, although this can be prolonged in renal failure.
Protamine sulphate – the anticoagulant effects of LMWH are not completely reversed by protamine sulphate, but this drug should be considered if patients are suffering significant haemorrhage following recent (<12 hours) administration of a therapeutic dose of LMWH.
Protamine doses are the same as for reversal of unfractionated heparin (1mg of protamine per 1mg of enoxaparin or 100units of dalteparin or tinzaparin), but may need to be repeated as further LMWH is released from its subcutaneous depot.
Oral warfarin reversal
Life-threatening haemorrhage (e.g. intracranial, GI)
All patients, including those with prosthetic heart valves, should have their anticoagulation completely reversed (aiming for normal PT and APTT) in the presence of life-threatening haemorrhage or trauma.
- Stop warfarin
- Give phytomenadione (Vitamin K1) IV 5mg (in 100ml glucose 5% over 15 – 30 minutes).
- Give intravenous prothrombin complex concentrate (Beriplex®)
- Dose according to table 1 below. Maximum dose is 5000units (200ml).
- Reconstitute 500unit vial of Beriplex® to 20ml using the sterile water and the reconstitution device supplied.
- Infuse immediately at an infusion rate not exceeding 8ml/minute.
- Contraindicated in patients with allergy to heparin, citrate or with suspected heparin-induced thrombocytopenia, and use with extreme caution in patients with disseminated intravascular coagulation (DIC) or recent (<1 month) venous thromboembolism, myocardial infarction or thrombotic stroke.
Table 1 – Beriplex® dose adjustment according to INR
|2 – 3.9
||1ml/kg=25 International units/kg
|4 – 6
||1.4ml/kg=35 International units/kg
||2ml/kg=50 International units/kg
- If INR is 1.5–1.9, consideration can be given to administering a small dose of Beriplex® (e.g. 12.5 International units/kg = 0.5ml/kg).
- Recheck coagulation status after 20 – 30 minutes and at 4–6 hours and 24 hours (or earlier if clinically indicated). Further doses of phytomenadione (Vitamin K1) may be required in cases of extreme overdose.
- When haemostasis has been secured, consideration should be given as to whether anticoagulation should be restarted. If restarting anticoagulant therapy, this would normally involve prophylactic doses of LMWH initially, gradually increasing to therapeutic doses before switching to an oral anticoagulant.
Less severe haemorrhage (e.g. haematuria, epistaxis)
- Stop warfarin for 1 – 2 days, until INR has fallen to therapeutic levels and bleeding has stopped.
- Give phytomenadione (Vitamin K1) 0.5–1mg IV. Use an insulin syringe to measure required volume before adding to 100ml glucose 5% and infusing over 15 – 30 minutes. N.B.: 0.5mg=0.05ml. 1mg=0.1ml.
- Re-assess regularly.
Asymptomatic INR >8 or INR 5 – 8 and high bleeding risk (e.g. recent surgery)
- Stop warfarin, monitor INR, and do not restart until INR <5.
- Consider giving phytomenadione (Vitamin K1) 0.5mg IV or 2mg orally (use paediatric IV formulation orally).
- Check INR the next day.
INR 5–8, asymptomatic
- Stop warfarin, monitor INR and restart warfarin when INR <5.
Reversal of direct oral anticoagulant (DOAC) agents
Direct oral anticoagulant agents available include:
- Dabigatran (Pradaxa®) – a direct Factor IIa (thrombin) inhibitor
- Rivaroxaban (Xarelto®) – a direct Factor Xa inhibitor
- Apixaban (Eliquis®) – a direct Factor Xa inhibitor
- Edoxaban (Lixiana®) – a direct Factor Xa inhibitor.
At the present time, only dabigatran has a reversal agent, Praxbind® (idarucizumab), which when administered at a fixed dose of 5mg IV should completely reverse its anticoagulant effect. Idarucizumab is available from the pharmacy emergency drug fridges at Glasgow Royal Infirmary, Queen Elizabeth University Hospital, Royal Alexandra Hospital and Inverclyde Royal Hospital. Further details on its use can be found on NHSGGC StaffNet / Clinical Info / Clinical Guidelines Directory and search for 'Dabigatran - management of haemorrhage, surgery and other invasive procedures' guideline. In renal impairment the half-life of dabigatran will be significantly prolonged, however, the drug can be cleared by dialysis.
The direct factor Xa inhibitors are not easily reversed, but fortunately they have relatively short half-lives (around 8 – 12 hours), although this could be prolonged in renal failure. Further guidance can be found on NHSGGC StaffNet / Clinical Info / Clinical Guidelines Directory and search for 'Apixaban, edoxaban and rivaroxaban: Management of haemaorrhage, surgery and other invasive procedures' guideline.
If patients receiving any of these new agents suffer major haemorrhage or require emergency surgery, then the following is recommended:
- Ascertain time of most recent dose of anticoagulant agent.
- Administer no further anticoagulant agent.
- Check coagulation screen (including PT, APTT and TCT) and renal function (U&Es). A normal PT and APTT does not necessarily exclude the presence of significant concentrations of these DOACs.
- Discuss urgently with your local haematologist.
- Maintain cardiovascular status with fluid, red cell and blood product support as necessary (refer to the Major Haemorrhage guideline).
- Consider possibility of delaying surgery until the anticoagulant effect has dissipated.
Further anticoagulant-specific advice can be found on NHSGGC StaffNet / Clinical Info / Clinical Guidelines Directory and search in the 'Haematology' section of the directory.
Reversal of Antiplatelet Therapy
- Commonly used antiplatelet agents (including aspirin, clopidogrel and prasugrel) cause irreversible platelet inhibition and therefore their effect may last up to 7–10 days following drug cessation. Ticagrelor may also cause prolonged platelet inhibition and increase peri-operative bleeding for up to 5 days after ingestion.
- If a patient suffers life-threatening bleeding while being treated with combination antiplatelet agents (e.g. aspirin and clopidogrel) consideration should be given to treatment with platelet transfusion. In vitro evidence suggests that such dual antiplatelet therapy may be temporarily overcome by treatment with 2–3 adult doses of platelets. Platelet transfusion will be more effective if deferred until at least 2 hours after aspirin ingestion and 12–24 hours after clopidogrel ingestion. Use of general haemostatic agents (e.g. tranexamic acid IV 1g) could also be considered.