Recommendations for use of specific reversal agents in major bleeding
| Anticoagulant . | Reversal agent . | Dose . | Kinetics of reversal/timing of repeated dosing . | Assessment of reversal . | Special considerations . |
|---|---|---|---|---|---|
| UFH | Protamine sulfate | 1 mg per 100 U of UFH given over the previous 4 hours; UFH half-life should be considered (ie, when UFH was stopped should be considered)11 | Dose should be maintained <100 mg over 2 hours; 50% of dose can be administered initially with subsequent doses titrated according to bleeding response8 | aPTT | Slow administration (≤5 mg/min) is advised to reduce the risk of protamine-induced hypotension and bradycardia11 |
| LMWH | Protamine sulfate | 1 mg for each 1 mg of LMWH given over the previous 4 hours; LMWH half-life should be considered (ie, when last dose of LMWH was given should be considered)11 | Dose should be maintained <100 mg over 2 hours; 50% of dose can be administered initially with subsequent doses titrated according to bleeding response8 | aPTT, PT, anti-Xa activity | Slow administration (≤5 mg/min) is advised to reduce the risk of protamine-induced hypotension and bradycardia11 |
| Partial reversal only, may be dependent on total sulfate content | |||||
| Coumarin | Vitamin K | 2.5 to 5 mg given orally (diluted in orange juice) or administered by IV over 30 minutes11 | 2 to 24 hours to improve INR depending on preparation; more rapid reversal is achieved by IV administration11,52 | INR, PT | There is a small risk of acute anaphylactoid reaction during IV use of vitamin K, even when this drug is administered slowly; thus, oral vitamin K is preferred in non-critically ill patients11 |
| Fresh frozen plasma, stored plasma, or cryosupernatant plasma | 15 mL/kg, 5 to 8 mL/kg may be appropriate when urgent reversal of therapeutic vs supratherapeutic INR is required11 | One-time dose | INR | Transfusion of blood products should be confined to patients in whom immediate reversal of overanticoagulation is needed (eg, active bleeding, imminent surgery)11 | |
| Prothrombin complex concentrate | Recommended doses range from 25 to 100 U/kg11,52 depending on product used | One-time dose | INR | Three-factor concentrates may not adequately correct the INR | |
| Recombinant factor VIIa | 10 to 90 μg/kg53-55 | Immediate effect53-55 | INR | Evaluated in case studies only; very short half-life may mandate serial doses | |
| Factor Xa inhibitors | Recombinant factor VIIa | 90 μg/kg56,57 | Immediate effect, duration 2 to 6 hours56,57 | aPTT, PT-INR, thrombin-generation time56,57 | Evaluated in healthy individuals not patients with active bleeding |
| Direct thrombin inhibitors | Desmopressin acetate | 0.3 μg/kg in normal saline IV over 15 minutes58,59 | Immediate effect, doses can be repeated at 8- to 12-hour intervals58 | INR, aPTT, thrombin times, clottable fibrinogen11 | Serial doses are associated with tachyphylaxis and hyponatremia and seizures, particularly in children <2 years of age58 |
| Cryoprecipitate | At least 10 units11 | Cryoprecipitate contains fibrinogen, factor VIII/von Willebrand factor, and factor XIII; 10 units will raise the fibrinogen by 0.7 g/L in the average-sized adult | |||
| Antifibrinolytic therapy (ϵ-aminocaproic acid, tranexamic acid) | ϵ-aminocaproic acid (Amicar) 0.1 to 0.15 g/kg IV over 30 min followed by infusion at 0.5 to 1 g/h until bleeding subsides or tranexamic acid (Cyklokapron) 10 mg/kg IV every 6 to 8 hours until bleeding subsides11 | ||||
| Fresh frozen plasma | Initial dose 2 units11 | Limited evidence for efficacy |
| Anticoagulant . | Reversal agent . | Dose . | Kinetics of reversal/timing of repeated dosing . | Assessment of reversal . | Special considerations . |
|---|---|---|---|---|---|
| UFH | Protamine sulfate | 1 mg per 100 U of UFH given over the previous 4 hours; UFH half-life should be considered (ie, when UFH was stopped should be considered)11 | Dose should be maintained <100 mg over 2 hours; 50% of dose can be administered initially with subsequent doses titrated according to bleeding response8 | aPTT | Slow administration (≤5 mg/min) is advised to reduce the risk of protamine-induced hypotension and bradycardia11 |
| LMWH | Protamine sulfate | 1 mg for each 1 mg of LMWH given over the previous 4 hours; LMWH half-life should be considered (ie, when last dose of LMWH was given should be considered)11 | Dose should be maintained <100 mg over 2 hours; 50% of dose can be administered initially with subsequent doses titrated according to bleeding response8 | aPTT, PT, anti-Xa activity | Slow administration (≤5 mg/min) is advised to reduce the risk of protamine-induced hypotension and bradycardia11 |
| Partial reversal only, may be dependent on total sulfate content | |||||
| Coumarin | Vitamin K | 2.5 to 5 mg given orally (diluted in orange juice) or administered by IV over 30 minutes11 | 2 to 24 hours to improve INR depending on preparation; more rapid reversal is achieved by IV administration11,52 | INR, PT | There is a small risk of acute anaphylactoid reaction during IV use of vitamin K, even when this drug is administered slowly; thus, oral vitamin K is preferred in non-critically ill patients11 |
| Fresh frozen plasma, stored plasma, or cryosupernatant plasma | 15 mL/kg, 5 to 8 mL/kg may be appropriate when urgent reversal of therapeutic vs supratherapeutic INR is required11 | One-time dose | INR | Transfusion of blood products should be confined to patients in whom immediate reversal of overanticoagulation is needed (eg, active bleeding, imminent surgery)11 | |
| Prothrombin complex concentrate | Recommended doses range from 25 to 100 U/kg11,52 depending on product used | One-time dose | INR | Three-factor concentrates may not adequately correct the INR | |
| Recombinant factor VIIa | 10 to 90 μg/kg53-55 | Immediate effect53-55 | INR | Evaluated in case studies only; very short half-life may mandate serial doses | |
| Factor Xa inhibitors | Recombinant factor VIIa | 90 μg/kg56,57 | Immediate effect, duration 2 to 6 hours56,57 | aPTT, PT-INR, thrombin-generation time56,57 | Evaluated in healthy individuals not patients with active bleeding |
| Direct thrombin inhibitors | Desmopressin acetate | 0.3 μg/kg in normal saline IV over 15 minutes58,59 | Immediate effect, doses can be repeated at 8- to 12-hour intervals58 | INR, aPTT, thrombin times, clottable fibrinogen11 | Serial doses are associated with tachyphylaxis and hyponatremia and seizures, particularly in children <2 years of age58 |
| Cryoprecipitate | At least 10 units11 | Cryoprecipitate contains fibrinogen, factor VIII/von Willebrand factor, and factor XIII; 10 units will raise the fibrinogen by 0.7 g/L in the average-sized adult | |||
| Antifibrinolytic therapy (ϵ-aminocaproic acid, tranexamic acid) | ϵ-aminocaproic acid (Amicar) 0.1 to 0.15 g/kg IV over 30 min followed by infusion at 0.5 to 1 g/h until bleeding subsides or tranexamic acid (Cyklokapron) 10 mg/kg IV every 6 to 8 hours until bleeding subsides11 | ||||
| Fresh frozen plasma | Initial dose 2 units11 | Limited evidence for efficacy |
UFH indicates unfractionated heparin; LMWH, low-molecular-weight heparin; aPTT, activated partial thromboplastin time; PT, prothrombin time; IV, intravenous; INR, international normalized ratio; ECT, ecarin clotting time.