Recombinant Factor VIIa Partially Reverses the Effects of Anticoagulants and Antiplatelet Agents on Thrombin Generation and Thromboelastography.

Commonly used anticoagulants and anti-platelet agents have the potential drawback of bleeding complications and some lack an antidote for their quick reversal. Recombinant factor VIIa (rFVIIa) has recently been suggested as a general hemostatic agent but its use has only been approved for hemophiliacs with inhibitors. The purpose of this study was to evaluate the in-vitro ability of rFVIIa to reverse the effects of the following anticoagulant and/or anti-platelet agents: aspirin/plavix (n=12), heparin/aspirin/plavix (n=10), and coumadin (n=10). The criteria for patient selection were as follows: adult patients receiving coumadin; INR≥2, adult patients receiving heparin; aPTT≥ 50 seconds. After IRB approval and informed consent, blood was collected from patients receiving these medications and the effects of rFVIIa were studied using the thrombin generation assay and rotational thromboelastography (RoTEG®). Primary hemostasis in whole blood was assessed using the Multiplate® platelet analyzer following stimulation with collagen (final concentration was 3.2 μg/ml). Patients in the aspirin/plavix and heparin/aspirin/plavix groups, but not the coumadin group, had significantly decreased platelet activation compared to the control group. In platelet-poor plasma, the lagtime for thrombin generation was increased in all patient groups receiving anticoagulants and/or antiplatelet agents but the time-to-peak thrombin concentration was increased only in the heparin/ASA/plavix and coumadin goups. The addition of rFVIIa (2 and 6 μg/ml) shortened the lagtime in all patient groups so that it was not significantly different from controls. In the coumadin group, the time-to-peak thrombin concentration was reversed with rFVIIa at 2 μg/ml but was not reversed in the heparin/aspirin/plavix group even at 6 μg/ml. The endogenous thrombin potential (ETP) was decreased only in patients receiving coumadin and could not be reversed at the highest concentration of rFVIIa (6 μg/ml). In whole-blood thromboelastography, the clotting time (CT) in the heparin/aspirin/plavix and coumadin groups were increased compared to controls. Addition of rFVIIa (6 ug/ml) reversed this anticoagulant effect in the coumadin group but not the heparin/aspirin/plavix group. The mean clot firmness (MCF) was decreased only in the heparin/aspirin/plavix group and addition of rFVIIa (6 ug/ml) reversed this effect. Although the number of patients collected in the heparin/aspirin /plavix group was 10, only 4 could be used in the final analysis for thrombin generation and thromboelastography since those with aPTTs>85 seconds did not achieve a CT nor did they generate sufficient thrombin to be evaluated in the allotted time (30 minutes for thromboelastography and 90 minutes for thrombin generation) The in vitro addition of rFVIIa (2 and 6 μg/ml) did not reverse this effect. This study shows that rFVIIa accelerates thrombin generation and CT, but does not completely reverse the effects of these agents on thrombin generation and thromboelastography.