Coagulopathy Reversal (Nonwarfarin Agents)

Basics

Patient on anticoagulant medications with clinically significant bleeding require close monitoring and anticoagulant reversal
Anticoagulant medication:
- Indirect inhibitors of thrombin:
  - Unfractionated heparin (UFH)
  - Low–molecular-weight heparin (LMWH)
    - Enoxaparin (Lovenox)
    - Dalteparin (Fragmin)
    - Tinzaparin (Innohep)
    - Ardeparin (Normiflo)
- 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 (Zontivity)
  - Thromboxane receptor antagonists:
    - Terutroban (Triplion)
  - 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
Dabigatran is FDA approved for VTE treatment in children 3 mo–12 yr of age
Argatroban and bivalirudin currently not FDA approved for pediatric use, but there are case reports of successful tx for thrombosis and alternative anticoagulation in setting of heparin-induced thrombocytopenia (HIT)

Excretion primarily renal with FXa inhibitors, dabigatran, and hirudin derivatives necessitating caution with impaired renal function
Polypharmacy should be evaluated as concomitant therapy with oral anticoagulant and antiplatelet therapy can increase major bleeding risk

Indirect inhibitors of thrombin:
- Up to 1/3 patients develop bleeding complication
- 2–6% of bleeding is major
- HIT can affect 5% of patients receiving heparin
Antiplatelet agents:
- >300 over-the-counter medications contain aspirin
- Conflicting studies regarding increased hematoma expansion and mortality
FXa inhibitors:
- Risk of major bleeding 46 per 1000 patient years
DTIs:
- Rate of major bleeding 3% per year

Indirect inhibitors of thrombin:
- Combines with antithrombin III to inactivate activated FXa. 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 COX-1 preventing formation of thromboxane A2, which inactivates platelets
  - Single dose suppresses for 1 wk
  - New platelet production recovers 10%/day
  - 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 half-life 8 hr
- Phosphodiesterase inhibitors:
  - Dipyridamole
  - 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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