EMed

Reversing anticoagulation

Bleeding while on oral anticoagulants increases significantly with INR (International Normalised Ratio) level > 5.0, particularly in patients with risk factors for bleeding.

Risk factors for bleeding include:

  • Age ( > 70) years
  • Previous bleeding complications
  • GI haemorrhage/ulcers
  • Hx CVA
  • Recent surgery
  • Uncontrolled BP
  • Recent initiation of anticoagulants

The majority of over-anticoagulated patients will return to their target therapeutic range within 3 days of discontinuing warfarin therapy.

PCC (Octaplex) dose in Major Bleed
Patients INR Dose PCC
INR 2 - 3.9 25 IU / Kg
INR 4 - 6 35 IU / Kg
INR > 6 50 IU / Kg

Print copy CUH 2014 Excessive Anticoagulation Policy.

Please check INR 30 mins post PCC infusion.

Summary

Drug Mech. of action Half-life Emergency Reversal
Warfarin Vitamin K antagonist 20-60 hours Vitamin K 5g IV ± PCC 25-50 U/kg
DOACs Mech. of action Half-life Emergency Reversal
Dabigatran Thrombin inhibitor 9 hours (renal fxn.) TXA 1g IV ± Idaruciumab (€) 5g IV
Rivaroxaban Factor Xa inhibitor 9 hours (renal fxn.) Andexanet (€ - haematology) or PCC 50 U/kg
Apixaban Factor Xa inhibitor Andexanet (€ - haematology) or PCC 50 U/kg
Edoxaban Factor Xa inhibitor Andexanet (€ - haematology) or PCC 50 U/kg
Antiplatelets Mech. of action Half-life Emergency Reversal
Aspirin Irreversibly inhibits COX1 5-7 days Platelet transfusion (low-level evidence). Desmopressin (caution with contraindications and limited evidence in trauma)
Clopidogrel Irreversible inhibits P2YI2 receptors 5-7 days Platelet transfusion (low-level evidence). Desmopressin (caution with contraindications and limited evidence in trauma)
Prasugrel Irreversible inhibits P2YI2 receptors 5-7 days Platelet transfusion (low-level evidence). Desmopressin (caution with contraindications and limited evidence in trauma)
Ticagrelor Irreversible inhibits P2YI2 receptors 5-7 days Platelet transfusion (low-level evidence). Desmopressin (caution with contraindications and limited evidence in trauma)
Dipyridamole Phosphodiesterase inhibitor 24 hours Platelet transfusion (low-level evidence). Desmopressin (caution with contraindications and limited evidence in trauma)

Vitamin K

Vitamin K1 (C31H46O2) and K2(C41H56O2)are two naturally occurring fat-soluble vitamins. Vitamin K is essential in the production of prothrombin.

  • Vitamin K is the first drug of choice to be administered for the reversal of excessive anti-coagulation if the patient has evidence of bleeding
  • Vitamin K is dispensed in ampoules of 1ml/10mgs known as Konakion® or 0.2mls/2mgs known as paediatric Konakion®. This can be administered sub-lingually using a 1ml syringe and a filter needle to draw up and administer the solution. Vitamin K is also available in 10mg tablets for oral administration
  • When partial correction is required to achieve a target therapeutic INR, the Intravenous preparation of Vitamin K can be administered in low doses of 1-2mgs sub-lingually
  • 5mgs of Vitamin K will completely reverse anticoagulation, which is only indicated if the patient is presenting with bleeding as a result of a high INR
  • Particular caution is advised for patients with prosthetic heart valves, where the use of vitamin K may increase the risk of thrombosis due to overcorrection of the INR. Therefore, if indicated, small doses of vitamin K only (e.g. 1 – 2 mg) are recommended
  • Prothrombin Complex Concentrate (PCC) is not routinely administered to reverse excessive anticoagulation in the absence of bleeding but should be administered in life threatening major haemorrhage
  • PCC is more effective than Fresh Frozen Plasma (FFP) for reversal of bleeding associated with excessive anticoagulation; therefore FFP is not indicated or recommended when PCC is available

Please discuss cardiac valve patients with cardiology BEFORE reversing warfarin.

Procedure

INR Action
3 < INR < 5
  1. ↓ Warfarin dose or stop (for 1 -2 days)
  2. Restart Warfarin ( reduced dose) when INR < 5
5 < INR < 8
No bleeding
  1. Stop Warfarin
  2. Recheck INR after 1-2 days
  3. If there are risk factors for bleeding recheck INR level within 24hrs
  4. Restart warfarin at reduced dose when INR < 5.0
  5. Determine if there are any causative or contributing factors for the increase in the INR level and adjust dose accordingly
5 < INR < 8
minor bleeding
  1. Stop warfarin for 1-2 days
  2. Consider administration of low dose Vitamin K 1-2mgs sub-lingually. depending on extent of bleeding and risk factors for further bleeding. A low dose of vitamin K e.g.1-2mgs of the paediatric intravenous preparation, can be administered sub-lingually. For patients with prosthetic heart valves caution should be taken to avoid over correction of the INR below therapeutic range
  3. Restart warfarin at reduced dose when INR < 5.0
  4. Determine if there are any causative or contributing factors for the increase in the INR level and adjust dose accordingly
  5. If INR over corrected contact Haematology for dosing instructions and advise
INR > 8.0
  1. Stop Warfarin
  2. Identify additional risk factors for bleeding: increasing age (e.g. > 70 yr), previous bleeding event/complications (ulcers, wounds, post surgery)
  3. Check for evidence of minor bleeding: epistaxis, bleeding gums, haematuria, oozing wounds, haemoptysis, PR bleeding
  4. Administer 1-2mgs of Vitamin K sub-lingually. A low dose of vitamin K, e.g.1-2mgs of the paediatric intravenous preparation, can be administered sub-lingually. For patients with prosthetic heart valves caution should be taken to avoid over correction of the INR below therapeutic range.
  5. Recheck INR within 24hrs and restart warfarin at a reduced dose once INR < 5.0.
  6. If there are no risk factors identified or there is no evidence of minor bleeding recheck INR within 24hrs
  7. Determine if there are any causative or contributing factors for the increase in the INR level and adjust dose accordingly
  8. If INR remains > 8.0 after 24hours the dose of Vitamin K can be repeated
  9. If INR over corrected contact Haematology for dosing instructions and advise
Print copy CUH 2014 Excessive Anticoagulation Policy

Major or life threatening bleeding

  • Intracranial bleed
  • Retroperitoneal bleed/Intra-ocular bleed
  • Muscle bleed, with compartment syndrome
  • Pericardial bleed
  • Active bleed with hypotension or 3g fall in Hb

Emergency Reversal

  1. Stop warfarin
  2. Consult with Haematology and Cardio-thoracic consultant/registrar if mechanical valve in-situ
  3. Administer Prothrombin Complex Concentrate (PCC) Octaplex as per the manufactures instructions, refer to “Policy and Procedure for the Prescribing, Ordering and Administration of Prothrombin Complex Concentrates (PCC) in Cork University Hospital”
  4. Administer 10mgs of Vitamin K intravenously (IV Vitamin K will provide 70% correction of INR within 8 hours). For patients with prosthetic heart valves caution should be taken to avoid over correction of anti-coagulation below therapeutic range. A low dose of IV Vitamin K (1-2mgs) can be administered sub-lingually. Discuss with cardio-thoracic, cardiac or haematology consultant or registrar before administering Vitamin K.
  5. Note: there may be an increased risk of bleeding when obtaining intravenous access due to high INR
  6. Recheck INR within 30-mins to 1 hour of administration of PCC. There may be an initial correction of the INR shortly after administration of PCC however this may be temporary due to the half-life of factor VII in PCC
  7. The INR should be repeated 6hrs post administration of PCC and regularly until the patients INR is within their target range
  8. Further Vitamin K may be required
  9. Warfarin should be commenced once haemodynamically stable
  10. If INR over corrected contact Haematology for dosing instructions and advise

Reversing LMWH

  • Consider Protamine 10mg/1000iu heparin infused / lmwh to a max of 7.5ml (75mg)

Reversing DOACs

Reversing Dabigatran

Contact haematology SpR - re Idarucizumab.

Dabigatran is an oral direct thrombin inhibitor (DTI) licensed for stroke prevention in atrial fibrillation.

Unlike warfarin, the PT/INR response to Dabigatran is inconsistent and should not be measured.

The activated partial thromboplastin time (APTT) provides a qualitative measurement of the anticoagulant effect of Dabigatran. Knowledge of the time of last dose is important for interpretation of the APTT.

If a patient receiving Dabigatran presents with bleeding:

  • Omit/delay next dose of Dabigatran
  • Measure APTT and PT (consider DTI assay if available)
  • Consider charcoal, with sorbitol, if within 2 h of ingestion
  • Give TXA - 1 g IV if significant bleed (TXA infusion guide)
  • Involve haematology team re Idarucizumab or PCC
  • Maintain renal perfusion to aid excretion.
  • Dabigatran - low protein binding - removed by dialysis.

Reversing Rivaroxaban (Xarelto®)

The PT/INR/APTT responses to Rivaroxaban are not reliable.

  • Omit/delay next dose of Rivaroxaban
  • If available, use Andexanet alfa (for adults only)
  • Consider charcoal, with sorbitol, if within 2 h of ingestion
  • Discuss w haematol. re Andexanet or PCC at 50 IU / Kg

References

  • BaglinTP et al, on behalf of BCSH. Guidelines on oral anticoagulation (warfarin): third edition – 2005 update. British Journal of Haematology 2005: 132:277-285
  • BaglinTP et al, on behalf of BCSH. Guidelines on oral anticoagulation (warfarin): third edition. British Journal of Haematology 1998; 101:374-387
  • Baker et al. Warfarin Reversal: Consensus guidelines on behalf of the Australasian Society of Thrombosis and Haemostasis. Med J Australia 2004; 181: 492-497
  • Ansel et al. The pharmacology and management of Vitamin K antagonists. Chest 2004; 126: 204- 233S

Content By Dr Arina Kruis, Dr Íomhar O' Sullivan 22/09/2020. Last review Dr ÍOS 1/12/21.