PharmacologyTier 2Medical Sciences concept

Anticoagulant reversal agents (vitamin K, idarucizumab, andexanet alfa, PCC)

Core concept

Anticoagulant	Specific reversal	Non-specific
Warfarin	Vitamin K (phytomenadione)	Prothrombin complex concentrate (Prothrombinex-VF), FFP if PCC unavailable
Dabigatran	Idarucizumab (Fab fragment, binds dabigatran ~350x more avidly than thrombin)	Dialysis (small, ~35% protein-bound), activated charcoal if <2 h
Rivaroxaban, apixaban	Andexanet alfa (decoy factor Xa, catalytically inactive)	PCC 50 units/kg where andexanet is unavailable
Unfractionated heparin	Protamine 1 mg per 100 units of heparin given in the preceding 2-3 h (max 50 mg)
LMWH	Protamine - only ~60% reversal of anti-Xa activity
Fondaparinux	No antidote	rFVIIa considered
Thrombolytic	-	Cryoprecipitate (fibrinogen), tranexamic acid, platelets
Antiplatelet	-	Platelet transfusion is NOT beneficial in intracerebral haemorrhage (PATCH trial showed harm); desmopressin considered

Warfarin - the decision is driven by bleeding, not by INR alone

Situation	Action
Life-threatening / critical-site bleeding	Vitamin K 5-10 mg IV + PCC 25-50 units/kg, whatever the INR
Clinically significant bleeding	Vitamin K 5-10 mg IV + PCC
INR >10, no bleeding	Vitamin K 3-5 mg oral, withhold warfarin, recheck in 24 h
INR 4.5-10, no bleeding	Withhold, +/- vitamin K 1-2 mg oral

Vitamin K takes 6-12 h to work - PCC works in minutes but wears off in ~6-8 h. Give both, or the INR rebounds
PCC contains factors II, VII, IX, X plus proteins C and S - a small volume, unlike FFP (~15 mL/kg)

DOAC specifics

Establish the drug, the dose, the time of the last dose and the renal function before anything else - most patients need none of these agents, only time
Idarucizumab 5 g IV (2 x 2.5 g) - immediate, complete reversal
- *Rebound anticoagulation and re-bleeding hours later as dabigatran redistributes from peripheral tissue back into plasma; more pronounced and more prolonged in renal impairment* -> recheck the APTT/thrombin time and consider a second 5 g dose
Andexanet alfa - bolus then 2-hour infusion, dosed by agent, dose and timing
- ANNEXA-I (2024) - the first RCT of a DOAC reversal agent; less haematoma expansion, but a higher rate of thrombotic events (~10% vs 6%) and no clear functional benefit; stopped early for haemostatic efficacy
- It also interferes with anti-Xa assays and with heparin, so restarting anticoagulation is difficult - discuss before giving it
Restart anticoagulation as soon as haemostasis allows - the thrombotic risk that justified the drug has not gone away

Measure what you can: normal thrombin time excludes dabigatran; a normal anti-Xa level excludes clinically significant rivaroxaban/apixaban; normal APTT and PT do not exclude a DOAC
Ask first: does this bleed need reversal at all? Site (intracranial, retroperitoneal, pericardial, intraocular, airway), haemodynamics, and the ability to control it locally
Always add the basics: stop the drug, local haemostasis, tranexamic acid, transfusion, correct acidosis and hypothermia, activated charcoal if ingestion was within 2-4 hours
Warfarin over-anticoagulation - hunt the cause: antibiotics, amiodarone, azoles, NSAIDs, alcohol, diarrhoea, thyroid disease, heart failure, reduced vitamin K intake
Vitamin K given for over-anticoagulation makes the patient warfarin-resistant for days - relevant if a mechanical valve needs re-anticoagulation

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