The optimal dose of vitamin K varies, based on patient-specific factors such as comorbidities, metabolic and genetic variation, weight, age, and liver function. Doses as low as 0.5 mg IV or 1 mg oral vitamin K have been effective in reversing an elevated INR to a therapeutic range in nonlife-threatening situations.11,14,15 The American College of Chest Physicians (ACCP), which issued new guidelines in 2008, recommends doses of <5 mg for an INR >5 but <9 if there is a high risk of bleeding; 5 to 10 mg is the recommended dose for all patients with an INR ≥9. In cases of significant bleeding, a dose of 10 mg IV is recommended.16 Excessive vitamin K supplementation may lead to warfarin resistance, making it necessary to use much higher doses of warfarin down the road to achieve therapeutic INR levels.
Fresh frozen plasma (FFP) replaces functional vitamin K-dependent clotting factors that are decreased in patients taking warfarin. The suggested dose is 15 mL/kg,17,18 but patients must be monitored with coagulation laboratory values to assess the amount needed. One unit of FFP is roughly 250 mL, which corresponds to roughly 250 units of clotting factors.
FFP works to offset coagulopathy quickly. But because the plasma is frozen, it has to be thawed and blood type-matched, which is time-consuming. FFP transfusion also may be associated with infections, although the risk is generally believed to be minimal.17 Other limitations in using FFP include the large volume of fluid that must be administered—with the attendant risk of fluid overload—and the possibility of significant infusion reactions that may require slowing the infusion rate.19
Prothrombin complex concentrate (PCC) is pooled from donor plasma and lyophilized to a powder. It is then reconstituted for clotting factor replacement, and is available through the pharmacy rather than the blood bank.20 PCC is dosed in international units of factor IX, although it includes proportional amounts of factors II, VII, and X and proteins C and S. The typical recommended dose is 30 to 50 U/kg.20,21
Although PCC contains human coagulation factors, it does not involve the same risks of fluid overload or infectious transmission as FFP. It can be given IV over 5 to 10 minutes. The risk of thrombogenicity has been reported in patients with hemophilia who receive PCC,22 but studies of PCC use in warfarin reversal have not shown this adverse effect.23,24 Data from the use of PCC for the treatment of hemophilia suggest that the risk of thromboembolic events begins with daily doses >200 U/kg. There is limited information about the safety of giving PCC to patients with mechanical valve replacement, pregnant women, and those in other high-risk situations.
Recombinant activated factor VII (rFVIIa) is also effective in reversing elevated INR.25,26 It replaces 1 of the clotting factors that is decreased in anticoagulated patients (factor VII), but the significance of not replacing factors II, IX, and X is unknown.27 The recommended quantity of rFVIIa ranges from a single dose of 1200 mcg to weight-based dosing (10-160 mcg/kg).25,28-30 (IV vitamin K and FFP are also given in emergent situations in which rFVIIa is administered.) Thrombogenicity is a possible complication with the use of rFVIIa, but data are scarce regarding the incidence of adverse effects.
Neither PCC nor rFVIIa has US Food and Drug Administration approval for use in reversing warfarin-induced anticoagulation. Their use for this purpose may be warranted only in situations that threaten life or limb, and must be guided by clinical judgment.
TABLE 2
How fast? Reversal agents and time of action32
| SPEED/TYPE OF REVERSAL REQUIRED | WHAT TO USE |
|---|---|
| Rapid (complete; within 10-15 minutes) | PCC or rFVIIa + vitamin K IV |
| Fast (partial) | FFP + vitamin K IV |
| Prompt (4-6 hours) | Vitamin K IV |
| Slow (within 24 hours) | Oral vitamin K |
| Ultra-slow (over a period of days) | Omit warfarin dose (no vitamin K) |
| FFP, fresh frozen plasma; PCC, prothrombin complex concentrate; rFVIIa, recombinant activated factor VII. | |
Severity of bleeding as a treatment guide
Studies of methods used to reverse warfarin’s anticoagulation effect are difficult to compare because of a lack of a standardized approach to the classification of bleeds.18,31,32 We’ve used the following classification system, modified from that of Fihn et al,31 to avoid confusion and inform treatment decisions:
- Minor bleed: Reported, not requiring additional testing
- Major bleed: Requiring medical evaluation and inpatient treatment and/or blood transfusion
- Life-threatening bleed: Leading to cardiac arrest, surgical/angiographic intervention, or irreversible sequelae (loss of limb/sight).