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The reversal of anticoagulation in clinical practice 

Sally Thomas and Michael Makris
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DOI: https://doi.org/10.7861/clinmedicine.18-4-314
Clin Med August 2018
Sally Thomas
ADepartment of Oncology and Metabolism, University of Sheffield, Sheffield, UK
BDepartment of Haematology, Royal Hallamshire Hospital, Sheffield, UK
Roles: NIHR clinical lecturer in haematology, honorary specialist registrar in haematology
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Michael Makris
CDepartment of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK
DDepartment of Haematology, Royal Hallamshire Hospital, Sheffield, UK
Roles: professor of haemostasis and thrombosis
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  • For correspondence: m.makris@sheffield.ac.uk
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    Fig 1.

    Representation of stage of action of anticoagulants and their reversal agents on a schematic clotting cascade. This diagram is intended to summarise drug actions but does not reflect the complexity of haemostasis believed to occur physiologically, where cell surface molecules regulate ­initiation, amplification and propagation of thrombus.31 Please see the main text for details on specific drug and reversal agent mechanisms. PCC = prothrombin complex concentrate; LMWH = low-molecular-weight heparin; UFH = unfractionated heparin; → = promotes; = suppresses

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    Table 1.

    Key pharmacokinetic features of common anticoagulant drugs

    NameExcretionPlasma half-life
    WarfarinHepatic metabolism to inactive metabolites excreted in urineEffective half-life 40 h
    UFHRapid endothelial cell internalisation (saturateable), slower renal clearance45–90 min
    LMWHPredominantly renal4 h
    Fondaparinux70% renal17–21 h
    ArgatrobanHepatic45 min
    Dabigatran80% renal13 h
    Apixaban25% renal, 75% hepatic12 h
    Edoxaban35% renal, 65% hepatic10–14 h
    Rivaroxaban25% renal, 75% hepatic5–9 h
    • LMWH = low-molecular-weight heparin; UFH = unfractionated heparin

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    Table 2.

    Approximate time prior to surgery or invasive procedure for which anticoagulant drug should be stopped. National4 and local guidelines and product literature should be consulted for specific details

    DrugDuration between stopping and invasive procedure or surgeryDuration before stopping and invasive procedure or surgery in impaired renal function – creatinine clearance <30
    Low bleeding risk procedureHigh bleeding risk procedureLow bleeding risk procedureHigh bleeding risk procedure
    Warfarin5 days
    UFH4 hours
    LMWHProphylactic dose, 12 hoursIf used, discuss dose and timing with haematology
    Treatment dose, 24 hours
    Fondaparinux24–42 hoursIf used, discuss dose and timing with haematology
    Argatroban4 hours
    Dabigatran24 hours48 hoursCr Cl > 50 to <80: 24–48 hoursCr Cl > 50 to < 80: 48–72 hours
    Cr Cl > 30 to <50: 48–72 hoursCr Cl > 30 to <50: 72–96 hours
    Apixaban24 hours48 hours48 hours72 hours
    Edoxaban24 hours48 hours48 hours72 hours
    Rivaroxaban24 hours48 hours48 hours72 hours
    • LMWH = low-molecular-weight heparin; UFH = unfractionated heparin

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    Table 3.

    Current drug-specific reversal strategies and novel agents under development

    DrugDrug-specific reversal strategyAgents likely to be available in the future
    Vitamin K antagonistsVitamin K, four-factor PCC
    Unfractionated heparinProtamine sulphateCiraparantag
    Low molecular weight heparinProtamine sulphateAndexanet alfa, Ciraparantag
    FondaparinuxConsider recombinant activated factor VIIAndexanet alfa, Ciraparantag
    DabigatranIdarucizumabCiraparantag
    Factor Xa inhibitorsFour-factor PCCAndexanet alfa, Ciraparantag
    • PCC = prothrombin complex concentrate

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    Table 4.

    Effect of direct thrombin antagonists and Xa inhibitors on clotting tests, and drug-specific assays

    DrugPTAPTTTTDrug specific assay
    NormalProlongedNormalProlongedNormalprolonged
    DabigatranBelow or within therapeutic levelsSupra-therapeutic levelsBelow or within therapeutic levelsWithin or above therapeutic levelsLikely little or no drug presentCannot interpretDilute thrombin time or ecarin clotting time
    RivaroxabanTherapeutic levels unlikely but cannot be excludedTherapeutic or supratherapeutic levelsTherapeutic or subtherapeutic levelsTherapeutic or supratherapeutic levelsUnaffectedRivaroxaban-specific anti Xa activity
    ApixabanInsensitive, cannot be assessed with these methodsUnaffectedApixaban-specific anti Xa activity
    EdoxabanTherapeutic levels cannot be excludedNot usefulUnaffectedEdoxaban-specific anti Xa activity
    • APTT = activated partial thromboplastin time; PT = prothrombin time; TT = thrombin time

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The reversal of anticoagulation in clinical practice 
Sally Thomas, Michael Makris
Clinical Medicine Aug 2018, 18 (4) 314-319; DOI: 10.7861/clinmedicine.18-4-314

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The reversal of anticoagulation in clinical practice 
Sally Thomas, Michael Makris
Clinical Medicine Aug 2018, 18 (4) 314-319; DOI: 10.7861/clinmedicine.18-4-314
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