Anti-thrombotic and haemorrhagic effects of active site-inhibited factor VIIa in rats

Active site-inhibited factor VIIa (FFR-rFVIIa) competes with factor VIIa (F VIIa) for binding to tissue factor (TF) and exerts an anti-thrombotic effec t. We report an evaluation of the anti-thrombotic properties of FFR-rFVIIa in a model of thrombosis involving two thrombogenic surfaces. Uncoated glas s capillaries or glass capillaries coated with TF were incorporated into an arterioarterial shunt in the rat and the occlusion time (OT) of the shunt was determined. An anti-thrombotic activity of FFR-rFVIIa was shown only on the TF-coated surface: the OT of the shunt was significantly prolonged, fr om 167 +/- 34 s in control animals to 312 +/- 42 s after i.v. bolus adminis tration of 4 mg/kg FFR-rFVIIa. This OT was similar to those observed with t he uncoated shunts in untreated animals (353 +/- 84 s). In vitro preincubat ion of the TF-coated shunt with FFR-rFVIIa significantly prolonged the OT t o 245 +/- 45 s in the absence of detectable amounts of FFR-rFVIIa in the pl asma. rFFR-rFVIIa weakly prolonged the tail template bleeding time by a fac tor of 1.5. This effect was more pronounced in animals pretreated with hepa rin. The anti-thrombotic and prohaemorrhagic effects of FFR-rFVIIa were tot ally reversed by administration of an equidose of rFVIIa. These results pro vide new information on the pharmacological properties of FFR-rFVIIa that w ill be useful for its clinical development.