Major bleeding during oral anticoagulant therapy associated with factor V activation by factor Xa.

OBJECTIVE Plasma thrombin generation (TG) provides important information on coagulation status; however, current TG output parameters do not predict major bleeding of patients on anticoagulants. We recently reported that FV activation by FXa contributes importantly to the initiation phase of TG. Here we investigated how this pathway varies in the normal population and whether FXa-mediated activation of FV is associated with major bleeding in patients on anticoagulant therapy. APPROACH We employed TIX-5, a specific inhibitor of FV activation by FXa, to estimate the contribution of FXa-mediated FV activation to tissue factor (TF) initiated TG. RESULTS We show that the contribution of this pathway to plasma TG varies considerably in the normal population, as measured by the time needed to form the first traces of thrombin (TG lagtime; mean prolongation by TIX-5 40%, range 0% to 116%). Comparing patients on vitamin K antagonists of the BLEED study (263 patients cases with and 538 patients without major bleeding), showed a marked prolongation in the median TG lagtime in the presence of TIX-5 in cases (12.83 versus 11.00 minutes, P=0.0030], while the TG lagtime without TIX-5 did only show a minor although significant difference (5.83 versus 5.67 minutes, P=0.0198). The TIX-5 sensitivity (lagtime+TIX-5/lagtime+vehicle) in the upper quartile was associated with a 1.62-fold (95%Cl 1.04-2.52) increased risk of major bleeding compared with the lowest quartile. CONCLUSION A greater dependence on FXa-mediated activation of FV of TG is associated with increased risk of major bleeding during VKA therapy.