Reversal of Antithrombotic Therapies

General management and drug therapy

Heparin reversal

Intravenous unfractionated heparin

• Stop heparin. It has a short elimination half-life of 30–90 minutes, although may be longer in renal failure.
• Protamine sulphate – this is only required in severe bleeding cases where there is likely to be a large amount of circulating heparin. Protamine sulphate 1mg neutralises 100units of heparin.

  Administer protamine up to a maximum of 50mg in a single dose as slow IV infusion over 10 minutes (anaphylaxis has been reported, see the Anaphylaxis guideline for management). Avoid protamine in patients with allergies to fish or fish products.

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

• 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:

• Direct Factor IIa (thrombin) inhibitor - dabigatran 
• Direct Factor Xa inhibitor - apixaban, edoxaban, rivaroxaban

Life-threatening haemorrhage

Reversal agents are now available for dabigatran and Factor Xa inhibitors. Andexanet alfa is licensed for the reversal of apixaban and rivaroxaban in cases of life-threatening or uncontrolled bleeding. Use of andexanet alfa for the reversal of edoxaban is off-label. Idarucizumab is licensed for the reversal of dabigatran in life-threatening or uncontrolled bleeding, or for preparation for emergency or urgent procedures.

Management of bleeding in patients taking DOACs will often remain challenging. Andexanet alfa and idarucizumab should only be used following discussion with haematology consultant with full guidance available below: 

• Apixaban, Edoxaban and Rivaroxaban (Factor Xa inhibitors): Management of haemorrhage, surgery, or other invasive procedures.
• Dabigatran, Management of haemorrhage, surgery and other invasive procedures.

Supply of either andexanet alfa or idarucizumab is available from the pharmacy emergency drug fridges at Glasgow Royal Infirmary, Queen Elizabeth University Hospital, Royal Alexandra Hospital and Inverclyde Royal Hospital.

If patients receiving any of the DOACs 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 haematology consultant.
• Maintain cardiovascular status with fluid, red cell and blood product support as necessary (see the Major Haemorrhage guideline).
• Consider the possibility of delaying surgery until the anticoagulant effect has dissipated.

Further anticoagulant-specific advice can be found in the full guidelines linked below. 

Less severe haemorrhage

For the management of less severe haemorrhage in patients taking a DOAC, see full guidelines: 

• Apixaban, Edoxaban and Rivaroxaban: Management of haemorrhage, surgery, or other invasive procedures.
• Dabigatran, Management of haemorrhage, surgery and other invasive procedures.

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.