Coagulopathy Reversal (Nonwarfarin Agents)



  • Patient on anticoagulant medications with minor, major, or clinically significant bleeding needing close monitoring +/– anticoagulant reversal
  • Anticoagulant medication:
    • Indirect inhibitors of thrombin:
      • Unfractionated heparin (UFH)
      • Low–molecular-weight heparin (LMWH)
        • Enoxaparin (Lovenox)
        • Dalteparin (Fragmin)
        • Tinzaparin
    • Antiplatelet agents:
      • Platelet aggregation inhibitors:
        • Aspirin
        • Clopidogrel (Plavix)
        • Cangrelor (Kengreal)
        • Cilostazol (Pletal)
        • Dipyridamole (Persantine)
        • Prasugrel (Effient)
        • Ticlopidine (Ticlid)
        • Ticagrelor (Brilinta)
      • Glycoprotein platelet inhibitors (GP IIb/IIIa):
        • Abciximab (ReoPro)
        • Eptifibatide (Integrilin)
        • Tirofiban (Aggrastat)
      • Protease-activated receptor-1 antagonists:
        • Vorapaxar
      • Unknown mechanism for reduction in platelets:
        • Anagrelide (Agrylin)
    • Factor Xa inhibitors (FXa inhibitors):
      • Fondaparinux (Arixtra)
      • Rivaroxaban (Xarelto)
      • Apixaban (Eliquis)
      • Edoxaban (Savaysa)
      • Betrixaban (Bevyxxa)
    • Direct thrombin inhibitors (DTIs):
      • Argatroban (Acova)
      • Bivalirudin (Angiomax)
      • Dabigatran (Pradaxa)
      • Hirudin derivatives:
        • Desirudin (Iprivask)
        • Lepirudin (Refludan)

Pediatric Considerations
  • Heparin and LMWH are the most commonly utilized anticoagulants beyond warfarin
  • Routine use of DTIs is being studied while currently in use in the setting of heparin-induced thrombocytopenia (HIT)

Geriatric Considerations
Excretion primarily renal with FXa inhibitors, dabigatran, and hirudin derivatives necessitating caution with impaired renal function


Incidence and Prevalence Estimates
  • Indirect inhibitors of thrombin:
    • Up to 1/3 patients develop bleeding complication
    • 2–6% of bleeding is major
  • Antiplatelet agents:
    • >300 over-the-counter medications contain aspirin
    • Conflicting studies regarding increased hematoma expansion and mortality
  • FXa inhibitors:
    • Unknown
  • DTIs:
    • Unknown


  • Indirect inhibitors of thrombin:
    • Combines with antithrombin III to inactivate activated FXa and also inhibits thrombin
    • LMWH has a reduced ability to inactivate thrombin
    • Half-life is dose dependent (30–150 min), can be up to 8 hr with LMWH
  • Antiplatelet agents:
    • Cyclooxygenase-1 (COX-1) inhibitors (Aspirin):
      • Inactivates cyclooxygenase-1 (COX-1) preventing formation of thromboxane A2, which inactivates platelets
      • Single dose suppresses for 1 wk
      • New platelet production recovers 10%/d
      • Patients may manifest normal hemostasis with as few as 20% platelets with normal COX-1 activity
      • Aspirin half-life 15–30 min
    • ADP antagonists (thienopyridines):
      • Inhibit the ADP-dependent pathway of platelet activation
      • Clopidogrel (Plavix) half-life 8 hr
    • Phosphodiesterase inhibitors:
      • Dipyridamole (Persantine)
      • Inhibits adenosine uptake and cyclic GMP phosphodiesterase activity, thus decreasing platelet aggregability
    • GP IIb/IIIa inhibitors:
      • Prevents cross-linking of platelets
  • FXa inhibitors:
    • Binds to antithrombin III, catalyzing FXa inhibition
    • No direct inhibitory effect on thrombin
    • Half-life 5–21 hr in normal renal function
  • DTIs:
    • Competitively targets active site of thrombin +/− exosite (substrate binding site)
    • Half-life long with dabigatran (14–17 hr) and short with others (20–45 min)

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