Summary
Direct thrombin inhibitors have proven efficacious in prevention of venous thromboembolism.
Bleeding complications are rare, but in case of acute serious bleeding, an effective
and instant haemostatic intervention may be required. In the present study it was
demonstrated that the direct thrombin inhibitor melagatran induces dose-dependent
abnormalities in whole blood (WB) clotting profiles as recorded bya recently described
modified thrombelastographic model, and that rFVIIa or APCC are capable of improving
the haemostatic capacity. Experiments were performed using WB from 30 healthy males.
In-vitro titration experiments (n=10) with addition of melagatran to WB corresponding
to plasma concentrations ranging from 0 to 5.0 µM (12 steps) showed a dose-dependent
prolongation of the clot initiation and characteristic decrease of the maximum rate
of clot propagation. In-vitro intervention studies (n=20) were completed with four
different concentrations of melagatran as well as addition of four different levels
of rFVIIa or APCC. At all tested concentrations of melagatran, rFVIIa significantly
shortened the melagatran-induced prolonged clot initiation but induced only minor
improvements of the reduced clot propagation. In contrast, APCC significantly and
dose-dependently shortened the clot initiation and accelerated the clot propagation.
In conclusion, our thrombelastographic model appears useful for evaluating the effect
of direct thrombin inhibitors on dynamic WB clot formation and rFVIIa, but especially
APCC significantly improved theWB clot formation. The pronounced stabilizing effect
of APCC may be caused by its content of prothrombin and activated coagulation factors.
Keywords
Melagatran - recombinant factor VIIa - activated prothrombin complex concentrate -
thrombelastography
