Coagulopathy Reversal (Nonwarfarin Agents)

Description

• 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)

• 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)

Epidemiology

• 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

Etiology

• 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)