Anticoagulation

Therapeutic anticoagulation has a broad array of both:

This provides a general overview of therapeutic anticoagulation. Management of perioperative anticoagulation is covered Anticoagulants, and thromboprophylaxis is covered under Thromboprophylaxis.

Indications

Contraindications

Parenteral

Unfractionated Heparin

Cocktail of bovine or porcine, variable-length, mucopolysaccharides with three major mechanisms of action:

  • Potentiates antithrombin III
  • Neutralises thrombin
  • Neutralises Factor Xa

Key pharmacological properties:

  • Dosing varies depending on level of anticoagulation required:
    • 8-12 unit/kg/hr infusion
  • Requires monitoring:
    • Detectable through ↑ APTT or anti-Xa
    • High inter-individual variability

Reversal:

  • Cessation
    • Safe
    • Relatively rapid
  • Protamine

Protamine is an anticoagulant in excess doses.

Resistance:

  • Heparin resistance occurs when the APTT fails to ↑ despite very high doses of heparin
    Considered >25-30 U/kg/hr.
  • Causes include:
    • ↓ Antithrombin III
      Functional assay of <60% correlates with ↓ in vitro activity.
    • ↑ Heparin binding proteins
      • Are an acute phase reactant and so often elevated in the critically ill
      • Results in a greater amount of UFH required to achieve a therapeutic APTT
      • APTT correlates with degree of anticoagulation
    • ↑ Factor VIII
      • May occur due to:
        • Systemic inflammation
        • Pregnancy
        • Malignancy
        • Hepatic disease
        • Renal disease
      • Results in a greater amount of UFH required to achieve a therapeutic APTT
      • APTT does not correlate with degree of anticoagulation
        Also known as pseudo-heparin resistance.
      • Requires monitoring with anti-Xa
    • ↑ Heparin clearance
  • Management options:
    • Check an anti-Xa to quantify the heparin effect
    • Give more heparin
      • Cheap
      • Unlikely to over-correct
    • Supplemental antithrombin III
      • Goal to achieve >120% effect on functional assay
      • May be unpredictable
        Significant ↑ in APTT if large dose of heparin has been already given.
      • Options include:
        • FFP
          20mL/kg ↑ functional assay by 20-25%; so large volumes may be required.
        • Antithrombin III concentrate ~1.4%/unit/kg; generally given in 1000 unit increments.
          • Significantly ↓ volume compared with FFP
          • Expensive and limited availability
    • Alternative anticoagulation
      Generally a direct thrombin inhibitor:
      • Bivalirudin
      • Argatroban

Low Molecular Weight Heparin

Reversal:

  • Cessation
  • Protamine
    Reverses ~50% of total effect.
  • Andexanet alfa

Enteral

Vitamin K Antagonists

Prevent synthesis of vitamin K dependent clotting factors, and are functionally synonymous with the various flavours of warfarin.

Vitamin K dependent clotting factors include:

  • Factor II
  • Factor VII
  • Factor IX
  • Factor X

Key pharmacological properties:

  • Rapid and complete oral absorption
  • Highly inter- and intra-individual variability
  • Requires monitoring
    • Frequency varies depending on stability and compliance.
    • Detectable though ↑ PT and INR
  • Effective half-life 20-60 hours
  • Stable in renal failure
  • Substantial drug interactions
Warfarin Drug Interactions
Potentiation Inhibition
  • Alcohol
  • Anabolic steroids
  • Cimetidine
  • Cotrimoxazole
  • Erythromycin
  • Fluid vaccination
  • Isoniazid
  • Metolazone
  • Metronidazole
  • Miconazole
  • Omeprazole
  • Paracetamol
  • Phenytoin
  • Propranolol
  • Tamoxifen
  • Tetracycline
  • Quinidine
  • Barbiturates
  • Carbamazepine
  • Rifampicin
  • Vitamin K

Reversal:

  • Factor replacement
    • Indicated for rapid and complete reversal
    • Consumption of administered factors will result in anticoagulation
      Synthesis remains inhibited.
    • Options include:
      • 4-factor PCC
      • 3-factor PCC
        May still require FFP.
      • FFP
  • Vitamin K
    • Acts within ~6 hours
    • Sustained reversal
      Balanced against thrombotic risk.
    • High doses may cause significant warfarin resistance if it is recommenced

Direct Anticoagulants

Direct anticoagulants inhibit specific elements of the clotting cascade, either:

  • Factor Xa
    Inhibit free and prothrombinase-bound factor Xa.
    • Rivaroxaban
      • Contraindicated in renal failure
    • Apixaban
      • Appropriate in renal failure
    • Edoxaban
  • Thrombin
    • Dabigatran
      • Prodrug
      • Reversible direct thrombin inhibition
Rivaroxaban Dosing
Creatinine Clearance (mL/min) Non-valvular AF VTE
>49 20mg daily 15mg BD for 21 days, then 10-20mg daily
30–49 15mg daily
15–29 15mg daily
(Use with caution)
<15 Avoid Avoid
Apixaban Dosing
Non-valvular AF VTE Prevention VTE Treatment
5mg BD 2.5mg BD 10mg BD for 7 days, then 5 mg BD

NB: Dose ↓ to 2.5mg BD is recommended in AF if on haemodialysis, CrCL <30mL/min, or ⩾2 of:

  • Age ⩾80
  • Weight ⩽60kg
  • Cr >133μmol/L

Key pharmacological properties:

DOAC may be preferable to VKA for both VTE and stroke prevention in AF.

  • Are 60-80% renally cleared
    Apixaban is the notable exception, with only 25% of the drug renally cleared.
  • Hepatic metabolism is via CYP450 enzymes
  • Elimination half-life of 7-12 hours
  • Have fixed dosing
  • Do not require monitoring
    • ↑ Therapeutic time compared to VKA
    • ↓ ICH risk compared to VKA
    • No drug interactions

Monitoring:

  • Monitoring of anticoagulant effect is more difficult compared to VKA
  • Coagulation assays qualitatively assess the presence of a coagulation effect, but not the degree
    • ↑ APTT and ↑ TCT occurs with thrombin inhibition
      i.e. Dabigatran.
    • ↑ PT occurs with Factor Xa inhibition
      Requires an appropriate DOAC-sensitive reagent.
  • Specific drug assays are available, although drug levels corresponding to therapeutic anticoagulation are not widely available

Reversal:

  • Reversal options are limited
  • Dabigatran
    • Idrarucizumab 5g IV
      • Monoclonal antibody
      • Rapidly effective
    • Factor replacement
      Significantly ↓ efficacy.
    • Dialysis
      Limited efficacy, 2nd line to idrarucizumab.
  • Xa inhibitors
    • Andexanaet alfa 400mg IV bolus, then 4mg/min for 4 hours
      • Recombinant factor Xa, which acts as a decoy receptor for circulating inhibitor
      • Binds to rivaroxaban, apixaban, and enoxaparin

Technique

Complications

References

  1. Bersten, A. D., & Handy, J. M. (2018). Oh’s Intensive Care Manual. Elsevier Gezondheidszorg.
  2. Ansell J, Hirsh J, Poller L, Bussey H, Jacobson A, Hylek E. The Pharmacology and Management of the Vitamin K Antagonists. Chest. 2004;126(3):204S-233S. doi:10.1378/chest.126.3_suppl.204S
  3. Tran HA, Gibbs H, Merriman E, et al. New guidelines from the Thrombosis and Haemostasis Society of Australia and New Zealand for the diagnosis and management of venous thromboembolism. Medical Journal of Australia. 2019;210(5):227-235. doi:10.5694/mja2.50004