LITERATURE
General Principle: “HASHTI”
- Hold further doses of anticoagulant
- Consider Antidote
- Supportive treatment: volume resuscitation, inotropes, etc.
- Local or surgical Hemostatic measures: topical agents (aminocaproic acid, tranexamic acid)
- Transfusion (red cells, platelets, FFP as indicated)
- Investigate for bleeding source
Anticoagulant Reversal Agents:
| Agent | Dose | Comments |
| Vitamin K | 1-10 mg IV/PO, not SQ or IM | • Infusion reactions rare; administer over 20-30 min• Takes 6 (IV) to 24 (PO) hours to reverse warfarin• Large doses can cause warfarin resistance on resumption |
| Protamine Sulfate | 10-100 mg IV | • Full reversal of unfractionated heparin• 60%-80% reversal of LMWH• No reversal of fondaparinux |
| DDAVP/Desmopressin | 0.3 mcg/kg | • Consider use for antiplatelet medication reversal |
| Blood Products Platelets Fresh frozen plasma (FFP) Cryoprecipitate | 1 apheresis unit, 4-6 whole blood units, 1 acrodose unit10-15 mL/kg(1 unit: ~ 250 mL)1-2 “pools” (5-10 units)(10 units pooled: ~100 mL) | • Raise platelet count by 30-60 x 109/L• Goal platelet count 50 – 100 x 109/L (indication dependent)• Use for antiplatelet agent reversal• Replaces all factors, but cannot fully correct° Hemostasis usually requires factor levels ~30%° Factor IX may only reach 20%• May need repeat dose after 6 hours• Large volume, takes ~45 minutes to thaw and prepare• Replacement for fibrinogen, factor VIII, factor XIII, von Willebrand factor• Takes ~45 minutes to thaw and prepare |
| Prothrombin complex concentrates (PCCs) Kcentra (“Four Factor PCC”) FEIBA (Factor Eight Inhibitor Bypassing Activity) | 25-50 Units/kg 75 Units/kg | • Kcentra is specific antidote for warfarin (small volume infusion over 10-30 minutes)• FEIBA can be used for reversal of Xa inhibitors but must be used with caution• Risk of thrombosis 1.4%• Contraindicated with history of HITNOTE: PCC may partially correct PT/aPTT but will not affect anti-factor Xa activity and will not increase drug clearance; correlation of shortening PT/aPTT with reduction in bleeding risk is unknown |
| Recombinant Factor VIIa(rFVIIa, NovoSeven) | 90 mcg/kg | • Risk of thrombosis 5-10%• May need repeat dose after 2 hours |
| Reversal Agents for Oral Thrombin Inhibitors Idarucizumab (Praxbind) | 5 g IV | • Effect on bleeding not immediate! Median time from administration to bleeding cessation may be as long as 11 hours• Will likely correct aPTT but correlation of improved lab results with clinical outcomes is not established• Plasma dabigatran concentrations may increase 12-24 hours following reversal due to re-distribution from extravascular space• Risks and benefits of repeat administration are not known |
Definitions Used for Reversal Situations
Non-urgent: Reversal is elective (procedures >7 days away)
Urgent (without bleeding): Reversal needed within hours
Urgent (with bleeding): Emergency reversal
REVERSAL SUGGESTIONS
| Drug to Reverse | Non-Urgent | Urgent (without bleeding) | Urgent (with bleeding) |
| Antiplatelet AgentsAspirin, Dipyridamole (Persantine/Aggrenox), Clopidogrel (Plavix),Ticlopidine (Ticlid), Prasugrel (Effient), Ticagrelor (Brilinta) | • Discontinue agent 5-10 days prior to procedure | • Consider platelet transfusion prior to high risk bleeding procedures | • HASHTI• Platelet transfusion• Desmopressin (0.3 mcg/kg) |
| Warfarin (Coumadin) | • Hold warfarin until INR in therapeutic range | • Hold warfarin• Consider Vitamin K 2.5 mg PO or 1-2 mg IV infusion if rapid reversal required | • HASHTI• Give Vitamin K 10 mg IV infusion over 30 minutes• Give Kcentra if life-threatening bleeding or intracranial hemorrhageINR 1.5-3.9: 25 units/kg (max 2500 units)INR 4.0-6.0: 35 units/kg (max 3500 units)INR >6.0: 50 units/kg (max 5000 units)(FFP if Kcentra not available) |
| Heparin (UFH) | Time since last heparin doseProtamine dose for each 100 units of heparin administeredImmediate1 mg (or 25 mg fixed dose)30 minutes – 2 hrs0.5 mg (or 10 mg fixed dose)> 2 hours0.25 mg (or 10 mg fixed dose) | ||
| Low-Molecular-Weight HeparinsEnoxaparin (Lovenox), Dalteparin (Fragmin), Tinzaparin (Innohep) | • Hold day of procedure• Once-daily regimens: ½ dose day prior• Twice-daily regimens: Hold evening dose day prior | Time since last dose LMWHProtamine dose for each 100 units of dalteparin/tinzaparin or 1 mg enoxaparin administered< 8 hrs1 mg (or 50 mg fixed dose)8-12 hours0.5 mg (or 25 mg fixed dose)> 12 hrsNot likely useful (or 25 mg fixed dose) | |
| Fondaparinux (Arixtra) | • Hold day of procedure• Once-daily regimens: ½ dose day prior• Twice-daily regimens: Hold evening dose day prior | • Wait 12-24 hours if possible | • HASHTI• Consider rVIIa (90 mcg/kg) |
| Direct Thrombin InhibitorsArgatroban, Bivalirudin (Angiomax), Lepirudin | • Delay next dose or discontinue DTI | • HASHTI• FFP | • HASHTI• FFP• If life-threatening bleeding or ICH, consider PCC |
| Direct Thrombin Inhibitor with specific reversal reagentsDabigatran (Pradaxa) | • Delay next dose or discontinue inhibitor | • If ingested within 2 hours, administer activated charcoal• Consider emergent hemodialysis• For life-threatening bleeding or emergency surgery, consider idarucizumab (Praxbind) 5gm IV (requires approval)• If active life-threatening bleeding or ICH, consider PCC | |
| Direct Xa InhibitorsEdoxaban (Savasya), Rivaroxaban (Xarelto), Apixaban (Eliquis) | • Delay next dose or discontinue inhibitor | • If ingested within 2 hours, administer activated charcoal• If active life-threatening bleeding or ICH, consider KCentra 50 units/kg (maximum 5000 units), 25 units/kg (maximum 2500 units) for ICH | |