Anticoagulation

Specific drugs

Drug	MOA	Washout time	Washout time eGFR<30	Level?	Reversal
Apixaban	Direct Xa inhibitor Liver-excreted	48 hours	72 hours	Anti-factor Xa	Consider prothrombinex + FFP Andaxanet is not available in australia, needs RCTs. Factor Xa decoy protein Not dialysable
Rivaroxaban	Direct Xa inhibitor Renally-excreted	48 hours	72 hours	Anti-factor Xa PT	Consider prothrombinex + FFP Andaxanet is not available in australia, needs RCTs. Factor Xa decoy protein Not dialysable
Dabigatran	Direct thrombin inhibitor	2-4 days	5 days	TCT - sensitive APTT/PT	idarucizumab (Praxbind - $3500 USD) 5mg IV Safe, but 5% clot risk Binds direct to dabigatran Available here since 2016 Works within 15 minutes, 93% success rate Could consider dialysis
Warfarin	Vitamin K epoxide reductase inhibitor, which prevents gamma-glutamyl carboxylase from completing a vital step in synthesis of II, VII, IX, X. Also prevents protein C and S synthesis, which causes the paradoxical pro-thrombotic effects after commencing.	Five days	Five days	INR TCT - should be < 30 to proceed safely	Dose depends on INR but Prothrombinex 25-50 units/kg + vitamin K If prothrombinex contraindicated, can give FFP
Clopidogrel	Platelet P2Y(12) inhibitor - prevents platelet response to exogenous and endogenous ADP. ADP is normally used for cross-linking of fibrin and platelet activation.	7 days	7 days	No
Heparin	Enhances the action of antithrombin III, an endogenous protein which normally inactivates factors IIa (thrombin) and Xa, thus inhibiting both intrinsic and extrinsic pathways
Enoxaparin	Enhances binding of antithrombin to factor Xa, but with less anti-IIa activity than heparin

General non-reversal management of bleeding patient/patient on anticoagulants needing surgery:

• Decide how urgent surgery is!
• Check if anticoagulant effect is still present (level as above)
• Perform a risk assessment for coagulation risk
  • Presence of stents/valves
  • Previous stroke
  • Chadsvasc
  • Relevant haematological disorders
• Canulae, full bloods including coags, anticoagulant level, XM
  • Ensure consented for blood transfusion
• Resuscitation with blood (?MTP)
• Optimise kidney function
• Consider charcoal (if ingested <2 hours)
• Symptomatic control
  • PPI etc
  • Tranexamic acid
• Discuss with haematology early
  • Reversal options
    • Major bleeding and renal impairment
    • Major bleeding and supra-therapeutic level of blood
    • Urgent surgery required and therapeutic level of drug on board

Low-risk factors for thromboembolism (more than one factor doesn't necessarily make the patient high-risk)

• AF with CHADSVASC of 2 or less
• Cardiomyopathy without previous CVA
• Mechanical aortic valve without previous CVA
• Bioprosthetic heart valves without previous CVA
• Unprovoked DVT/PE >3/12 ago
• Rheumatic heart disease without previous CVA
• Permanent IVC filter

High-risk factors for thrombosis/thromboembolism

• Neurology
  • Previous CVA with AF or other cardiac source
  • CHADSVASC of 3 or higher
  • Arterial embolism <1 month
• Cardiology
  • Mechanical mitral or tricuspid heart valve
  • Mechanical aortic heart valve with AF, previous thromboembolism or LV dysfunction
  • Multiple mechanical heart valves
• Haematology
  • Recurrent DVT/PE
  • DVT/PE within 3/12
  • Provoked DVT/PE >3/12 ago where the precipitant is still present
  • History of DVT/PE with severe thrombophilia (protein C/S/antithrombin deficiency, or presence of antiphospholipid antibodies)
• Recent stent
  • Bare metal stent 6/52 - it's possible to cease the clopidogrel sooner
  • DES 12 months - should be on DAPT for all 12 months
  • Ceasing of DAPT prior to this window leads to a 20-30% risk of stent occlusion

Avoid ceasing aspirin

• Increases risk of bleeding by only 1.5x
• But reduces risk of cardiac events by 80%

Heparin (info based on Austin guidelines 2022 - varies depending on local lab protocols)

HITS

• IgG antibody-mediated adverse effect of heparin
• Can occur with either UFH or LMWH
• Investigate for HIT if any of the following occur between days 5 and 14 following initiation of heparin:
  • Fall in platelet count >30%, even if nadir remains >150 (generally occurs 5-10 days after starting heparin in heparin-naïve patients, and can be day of starting for heparin re-exposure)
  • Venous or arterial thrombosis
  • Cutaneous lesions at heparin injection sites
  • Acute systemic reactions
• Use 4TS score - very sensitive if score is low

Warfarin

• Vitamin K epoxide reductase inhibitor - competitively inhibits the hepatic synthesis of the vitamin K-dependent clotting factors II, VII, IX, X
• Can be reversed by simply replacing those factors with FFP or prothrombinex, and giving supplemental vitamin K to overcome the inhibition
• FFP only leads to a median reduction of INR of 0.2. Also, it can't be administered quickly, and you need a large volume.
• Prothrombinex - generally three-factor, containing II, IX and X; but some four-complex versions are available - can be rapidly reconstituted and reversed from its stored powder form. The volume is <100mL. The main disadvantage is cost. INR <1.3 at 30 minutes from start of treatment was achieved in 62% of prothrombinex group but only 10% of FFP group.
  • Three-factor prothrombinex is fine for INR <4, but it has been suggested that four-factor should be used when INR >4, or three-factor + FFP.
• Vitamin K IV results in a lower INR 4-6 hours after infusion (5-10mg diluted in 50mL N/S and given over 20 minutes)
• Prothrombinex doses

Initial INR	1.5-2.5	2.6-3.5	3.6-10	>10
Target INR 0.9-1.3	30IU/kg	35IU/kg	50IU/kg	50IU/kg
Target INR 1.4-2.0	15IU/kg	25IU/kg	30IU/kg	40IU/kg

DOACs

Apixaban (from Austin guideline 12/2/2018)

• Half-life 12 hours
• Apixaban/dabigatran/rivaroxaban level can be done - useful in reversal or to ensure complete removal from system
  • <30ng/ml are generally considered safe for surgery, while levels >400ng/mL are major rik of uncontrollable haemorrhage
• Reversal - MUST consult haem
  • No specific antidote and will not be removed by dialysis
    • Andexanet is in trial stage
  • Activated charcoal is useful if last oral dose was within 2/24
  • Option: Prothrombinex 50 units/kg with FFP 2 units, +/- recombinant factor VIIa
• Elective:

• Restart 48-72 hours post-op for high bleeding risk surgery

Dabigatran (Pradaxa)

• Taken from Austin guideline published 25/2/16
• Oral direct thrombin inhibitor
• Elimination half-life 12-17 hours. Eliminated at kidneys.
• Monitoring: PT and APTT are unreliable, but normal APTT suggests unlikely high levels of dabigatran.
  • Best available monitoring is thrombin clotting time (TCT) - if normal, excludes presence of dabigatran
  • HEMOCLOT is a dilute thrombin clotting time assay but doesn't correlate well with risk of bleeding
• Reversal: idarucizumab - monoclonal Ab, binds to dabigatran. Achieves rapid and complete reversal. Generally safe - 5% risk of thrombosis.
  • Approval required via either anaesthetist in charge or haem consultant on call
  • Used in life-threatening bleeding or for urgent surgery
  • Dose is 5g IV either bolus or infusion - see guideline for full order
  • Perform dabigatran levels and TCT both prior to, post, and 4 hours post administration
• Dialysis may enhance clearance
• Elective surgery:

• Recommence 48-72 hours post high risk surgery

Clopidogrel

• P2Y12 receptor blocker on platelets for ADP, which irreversibly prevents platelet activation
• No specific reversal agents

Thrombolysis/fibrinolysis

• Contraindications:
  • Active peptic ulcer
  • Previous haemorrhagic stroke
  • Recent head injury
  • Prolonged traumatic CPR