Optimizing warfarin reversal--an ex vivo study.
BACKGROUND
Warfarin reversal is a common clinical situation. This is commonly performed using vitamin K and, depending on the urgency, fresh frozen plasma (FFP), prothrombin complex concentrates (PCCs), or activated factor VII. Even though PCCs are widely used, the ideal dosing regimen is far from established.


OBJECTIVE
To verify differences in warfarin reversal patterns using FFP, recombinant FVIIa (rFVIIa), and PCC; and to test the hypothesis that supratherapeutic International Normalized Ratios (INRs) might not correlate with thrombin generation (TG) and identify the ideal concentrations of PCC required to reverse various INR thresholds.


METHODS
We studied the effects of FFP, rFVIIa and Beriplex P/N on the INR and TG, using the calibrated automated thrombography assay in ex vivo warfarinized plasma. Plasmas with different INRs were spiked with different concentrations of Beriplex P/N.


RESULTS
Beriplex P/N was the only agent that completely normalized TG and the INR. The endogenous thrombin potential (ETP) and the peak thrombin showed a significant negative correlation with all INRs. The ETP and velocity of TG reached a plateau at an INR of approximately 4.0. A concentration equivalent to a dose of 30 IU kg(-1) Beriplex P/N normalized the ETP, the INR, FII, FVII, FIX and FX of samples with INRs > or = 4.0. Higher doses resulted in hypercoagulable TG patterns. A concentration equivalent to a dose of 20 IU kg(-1) was sufficient to reverse warfarin at an INR range of 2.0-3.9, as judged by the same tests.


CONCLUSIONS
Warfarin reversal algorithms could be simplified with the adoption of this strategy utilizing two doses of PCC, depending on the INR of the patient. This would also lead to cost reductions and, possibly, a reduction in thrombotic risk.
Gatt
A
A
The Royal Free Hospital Haemophilia Centre & Thrombosis Unit, Hampstead, London, UK. alexander.gatt@royalfree.nhs.uk
Riddell
A
A
van Veen
J J
JJ
Kitchen
S
S
Tuddenham
E G
EG
Makris
M
M
D000925:Anticoagulants / Q000627:therapeutic use*; D006801:Humans; D019934:International Normalized Ratio; D014859:Warfarin / Q000627:therapeutic use*
D000925:Anticoagulants; D014859:Warfarin