Thrombin generation and thromboelastometry in monitoring the in-vitro reversal of warfarin: a comparison between 3-factor and 4-factor prothrombin complex concentrates

The efficacy of three-factor prothrombin complex concentrates (PCCs) in the reversal of vitamin K antagonists is still a matter of debate. We compared the 'in-vitro' effect of three PCCs (one three-factor and two four-factor) on international normalized ratio (INR), thrombin generation and thromboelastometry of patients at different degrees of anticoagulation with vitamin K antagonist. We tested three concentrations of PCC (0.5, 1 and 1.5 U/ml) in six patients: three (INR 2.0-2.9) and three (INR 3.0-4.0). In this preliminary phase, we determined the lowest effective dose for a target INR less than 1.5 and to normalize endogenous thrombin potential and clotting time in EXTEM assay. In the validation phase, we tested the effect of the newly determined lowest effective PCC dose on samples of 40 (INR 2.0-2.9) and 20 (INR 3.0-4.0) patients. The minimum efficacious dosage to achieve the target INR with three-factor PCC (3-PCC) was 0.5 (INR 2.0-2.9) and 1.5 U/ml (INR 3.0-4.0). Four-factor PCCs (4-PCCs) achieved target INR with the lowest dose (0.5 U/ml) independently of baseline INR. Thrombin generation endogenous thrombin potential and EXTEM clotting time achieved normal values with the lowest dose (0.5 U/ml) of either 3-PCC or 4-PCC independently of baseline INR. Data observed in the preliminary phase were confirmed in the validation phase. 3-PCC appears to be as effective as 4-PCC in reversing oral anticoagulant treatment based on thrombin generation and EXTEM data, but not INR data, at least in the range of INR considered in our study. Further studies are needed to address the clinical implications of our results.