Table 3.

Reversal and factor replacement agent characteristics.

Drug	Reversal or Replacement Target	Administration Window*	Mechanism	FDA Indications	Half-life	Dosing Regimen	Special Considerations and Cost†
Reversal
Idarucizumab	Direct thrombin (factor IIa) inhibitor (dabigatran)	<8–12 h	Humanized monoclonal antibody fragment; neutralizes the anticoagulant effect of dabigatran by irreversibly binding to it and its metabolites	Life‒threatening bleeding Need emergency surgery/urgent invasive procedure Specific for dabigatran	9.5–10.8 h	5–g (2 × 2.5 g vials) IV bolus	Redosing was used in ≈2% of patients ≈ $4,452 per administration
Andexanet alfa	Direct factor Xa inhibitors (apixaban and rivaroxaban)	<18 h	Recombinant modified human factor Xa (activated factor X) molecule, which acts as a decoy by reversibly binding to factor Xa inhibitors, thereby reducing their availability to act on endogenous factor Xa	Life-threatening or uncontrolled bleeding Specific for direct factor Xa inhibitors, approved only for apixaban and rivaroxaban	5–7 h	Low dose: ≥8 h since last dose or ≤ 5 mg of apixaban or ≤10 mg of rivaroxaban Initial IV bolus: 400 mg; target infusion rate of 30 mg/min; then IV infusion: 4 mg/min for up to 120 min High dose: <8 h since last dose or unknown and >5 mg of apixaban or >10 mg of rivaroxaban Initial IV bolus: 800 mg; target infusion rate of 30 mg/min; then IV infusion: 8 mg/min for up to 120 min	Low vs high dose based on timing from last dose and dosage amount of Xa inhibitor May need to redose, although no clinical data currently exist Low dose: ≈ $33,000 per administration High dose: ≈ $59,400 per administration
Protamine	UFH and LMWH (enoxaparin, dalteparin)	1–6 h (unfractionated heparin); SQ doses of UFH take longer to Absorb 3–12 h (low-molecular‒ weight heparin); SQ doses of LMWH take longer to absorb	A weak anticoagulant that binds heparin and forms inactive complex	Neutralization of heparin or low-molecular-weight heparin		Heparin: 1 mg of protamine will neutralize not less than 100 units of heparin; slow IV injection during 10 min, up to max of 50 mg/dose Dalteparin: 1 mg IV for every 100 anti-Xa IU of dalteparin Enoxaparin: 1 mg IV for every 1 mg of enoxaparin administered in the previous 8 h; if >8 h has elapsed since the last dose, a second infusion of 0.5 mg per 1 mg of enoxaparin may be given	≈ $10 to $133 per administration (50– to 450–mg range, with higher range representing average dosing in cardiothoracic surgery patients for UFH reversal)
Replacement
4‒factor PCC‡ (Kcentra in the US)	Approved use: vitamin K antagonists (warfarin) Nonapproved use: DOACs	Varies	Contains nonactivated vitamin K-dependent coagulation factors II, VII, IX, and X, and antithrombotic protein C and protein S, heparin, albumin	Urgent reversal of vitamin K antagonist therapy for treatment of major bleeding, surgical procedures, or both	Factor dependent: 4.2–59.7 h	Warfarin: individualize dose by INR and IBW: INR-based 25–50 IU/kg IV, max 2,500–5,000 IU with concurrent vitamin K or 1,500 IU ×l; may repeat 500 units if bleeding continues DOACs: life ‒ threatening or critical site: 10–25 units/kg and repeated dose in 1–2 h if bleeding continues or if clinically indicated. May consider 50 units/kg up to a suggested maximum of 100 units/kg Nonlife‒threatening or noncritical site: 10 units/kg ×l and repeated dose in 1–2 h if bleeding continues	Warfarin: coadminister with IV vitamin K DOAC: a median (interquartile range) dose of 2,000 IU (1,500–2,000 IU) typically given with less or more needed for patients under or over 65 kg, respectively. Contains heparin so should not be used in patients with confirmed or strongly suspected HIT z$5,075 to $20,300 per administration (25–100 units/kg=1,750 − 7,000 units)
3-factor PCC‡ (Profilnine SD and Bebulin VH in the US)	Factor replacement in patients with hemophilia B Not recommended for DOAC reversal†	Varies	Contains factors II, IX, and X	Hemorrhage in patients with hemophilia B	24–32 h	No. of factor IX IU required=body weight (kg) × desired factor IX increase (%)×l IU/kg	Not recommended for DOAC reversal ≈$2,818 to $11,270 per administration (25–100 units/kg=1,750–7,000 units)
aPCC‡ (FEIBA in the US)	Approved use: factor replacement patients with hereditary factors VIII and IX deficiency and nonhemophiliacs with acquired inhibitors to factors VIII, IX, and XI Nonapproved use: surgical coagulopathy such as trauma or cardiothoracic; DOAC bleeding reversal	Varies	Contains II, VII, IX, and X with primarily activated factor VII and nonactive factors II, IX, and X	Hemorrhage in patients with hereditary factor VII and IX deficiency disease with inhibitor; both for prophylaxis preprocedure and for active bleeding	72 h (factor II)	Maximum: single dose, 100 units/kg; daily dose, 200 units/kg DOACs: Life‒threatening or critical site: 10–25 units/kg and repeated dose in 1–2 h if bleeding continues or if clinically indicated. May consider 50 units/kg up to a suggested maximum of 100 units/kg Nonlife‒threatening or noncritical site: 10 units/kg ×l and repeated dose in 1–2 h if bleeding continues	≈ $4,725 to $18,900 per administration (25–100 units/kg=1,750 to 7,000 units)
Vitamin K	Vitamin K antagonists (warfarin)	Varies	Vitamin necessary for the hepatic synthesis of factors II, VII, IX, and X Cofactor for a microsomal enzyme that triggers the posttranslational carboxylation of peptide‒bound glutamic acid residues into active coagulation factor	Acquired hypoprothrombinemia and hypoprothrombinemia secondary to anticoagulant	NA	Nonbleeding patients: 2.5–25 mg PO to decrease INR Major bleeding: 5 to 10 mg slow IV injection, in addition to 4-factor PCC	Initial onset typically 3–6 h if given IV; maximal initial effect on INR usually occurs in ≈16–20 h For bleeding patients receiving warfarin, give vitamin K first and before 4F‒PCC (Kcentra) if 4F‒PCC used Oral: ≈ $67 to $353 per administration (5–25 mg PO) IV: $135 to $270 per administration (5–10 mg IV)
Fresh frozen plasma	Vitamin K antagonists (warfarin)	Varies	Comprised plasma proteins such as albumin, immunoglobulins, coagulation factors, complement proteins, and protease inhibitors	Acquired combined coagulation factor deficiency caused by liver disease, or undergoing cardiac surgery or liver transplant TTP	NA	10–15 mL/kg IV for replacement of coagulation factors in patients with acquired deficiencies	Thawing requires 15–30 min, depending on the quantity Likely ineffective for DOAC reversal ≈$168 per administration (4 units)
Other
Tranexamic acid	Not drug specific	NA	Competitive inhibitor of plasminogen activation	IV: patients with hemophilia for short-term use to reduce or prevent hemorrhage and reduce the need for replacement therapy during and after tooth extraction Oral: heavy cyclic menstrual bleeding	IV: 2 h PO: 11 h	Trauma: 1,000 mg administered IV during 10 min, followed by 1,000 mg infused during the subsequent 8 h	≈ $18 to $174 per administration (1,000–2,000 mg)

UFH, Unfractionated heparin; LMWH, low-molecular-weight heparin; US, United States; DOAC, direct oral anticoagulant; aPCC, activated prothrombin complex concentrate; TTP, thrombotic thrombocytopenic purpura.

^*Assumes normal renal and hepatic function and normal body mass index.

^†Cost based on typical initial administration for a 70-kg patient, according to the Medi-Span Average Wholesale Price as of June 2019. FFP price is based on a cost of $41.95 per unit (from Shander et al 65).

^‡Dosing of PCC/aPCC products is expressed as units of factor IX.