High-dose factor VIIa increases initial thrombin generation and mediates faster platelet activation in thrombocytopenia-like conditions in a cell-based model system

Clinical experience has shown that high doses of recombinant factor VIIa (r FVIIa) may ensure haemostasis in thrombocytopenic patients. We have used a cell-based model system to mimic thrombocytopenia and analyse the effect of rFVIIa. Lowering the platelet density from 200 x 10(9)/l (reflecting norma l conditions) to 100, 50, 20 and 10 x 10(9)/l revealed a platelet density-d ependent decrease in the maximal rate of thrombin generation, a prolongatio n in the time to maximal thrombin activity and a lower maximal level of thr ombin formed. The platelet activation, measured as the time to half-maximal P-selectin (CD62) exposure, was not significantly dependent on the platele t density in the range of 200 x 10(9)/l to 10 x 10(9)/l, although there was a tendency for slower platelet activation at 20 x 10(9) and 10 x 10(9) pla telets/l than at the higher platelet densities. Addition of 50-500 nmol/l r FVIIa to samples with 20 x 10(9) or 10 x 10(9) platelets/l shortened the la g phase of thrombin generation as well as the time to half-maximal platelet activation. Our data indicate that high doses of rFVIIa may help to provid e haemostasis in thrombocytopenic patients by increasing the initial thromb in generation, resulting in faster platelet activation and thereby compensa ting for the lower number of platelets present.