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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:3049-3056.)
© 1997 American Heart Association, Inc.

Articles

Antithrombotic Efficacy of Inactivated Active Site Recombinant Factor VIIa Is Shear Dependent in Human Blood

Una Ørvim; R. Marius Barstad; Lars Örning; Lizette B. Petersen; Mirella Ezban; Ulla Hedner; ; Kjell S. Sakariassen

From Nycomed Imaging AS, Oslo, Norway, and Novo Nordisk AS, Gentofte, Denmark (M.E., U.H.).

Correspondence to Kjell S. Sakariassen, Nycomed Imaging AS, Gaustadalléen 21, N-0371 Oslo, Norway. E-mail kjell.sakariassen{at}nycomed.telemax.no

Abstract Several studies have indicated a profound role for factor VII(a) [FVII(a)] in venous and arterial thrombogenesis. In the present study, we quantified the inhibitory efficacy of dansyl-glutamyl-glycyl-arginyl-recombinant FVIIa (DEGR- rFVIIa) on acute thrombus formation. Thrombus formation was elicited by immobilized tissue factor (TF) in a parallel-plate perfusion chamber device at blood flow conditions characterized by wall shear rates of 100 s^-1 (veins) and 650 s^-1 (medium-sized healthy arteries). Native human blood was drawn directly from an antecubital vein by a pump into a heparin-coated mixing device in which DEGR-rFVIIa (0.09 to 880 nmol/L final plasma concentration) or buffer was mixed homogeneously with flowing blood. Subsequently, the blood was passed over a plastic coverslip coated with TF and phospholipids in the parallel-plate perfusion chamber. Fibrin deposition, platelet-fibrin adhesion, and platelet thrombus volume triggered by this surface were measured by morphometry. DEGR-rFVIIa inhibited thrombus formation in a dose-dependent manner, but the efficacy was shear rate dependent. At a wall shear rate of 100 s^-1, the IC₅₀ (50% inhibition) was 30 nmol/L, whereas at 650 s^-1, the IC₅₀ was 0.6 nmol/L. Binding studies to immobilized TF under flow conditions using surface plasmon resonance revealed a significantly higher on-rate for DEGR-rFVIIa and FVIIa than for FVII, 2.8x10,⁵ 2.6x10⁵, and 1.8x10⁵ M^-1 s^-1, respectively. This indicates that a contributing factor to the shear-dependent efficacy may be a differential importance of on-rates at arterial and venous blood flow conditions.

Key Words: DEGR-rFVIIa • tissue factor • thrombus formation • blood flow

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