Future possibilities in the regulation of the extrinsic pathway: rFVIIa and TFPI

Following vessel wall injury, tissue factor (TF) is being exposed and forms complexes with the already activated FVII (FVIIa) present in the circulati ng blood, providing a limited amount of thrombin molecules that activate a number of coagulation proteins as well as the platelets. As a result of act ivation with thrombin the platelet surface exposes negatively charged phosp holipids to which activated coagulation proteins bind tightly, and full thr ombin generation occurs, resulting in the conversion of fibrinogen into fib rin. After the first FXa is formed, the tissue factor pathway inhibitor (TF PI) forms a complex with FXa. In the next step a quaternary complex is bein g formed, TF/FVIIa/FXa/TFPI, which inhibits the first step of the haemostat ic pathway. Recombinant FVIIa (rFVIIa) has been developed for use as a haem ostatic agent (NovoNordisk A/S, Denmark). Inactivated rFVIIa (rFVIIai) has also been prepared, and it has similar binding capacity to TF as rFVIIa but it blocks the catalytic activity of the TF complex. In various animal mode ls rFVIIai has been demonstrated to prevent or diminish immediate thrombus formation at the site of vessel wall injury (athroplasty or other forms of mechanical injury) as well as the development of long-term intima thickenin g. Also, topical application of rFVIIai was found to block the formation of a thrombus. rFVIIai was shown to have an anti-inflammatory effect in lipop olysaccharide (LPS)-induced sepsis, and postischaemic reperfusion injury wa s found to be reduced by the administration of rFVIIai. In a limited number of patients undergoing percutaneous transluminal coronary angioplasty (PTC A), rFVIIai was observed to allow PTCA to be performed at lower doses of he parin than what has been reported previously. Recombinant TFPI has been sho wn to attenuate the lethal inflammatory and coagulopathic response. Further more, topical application of rFVIIai has been found to increase the patency rate in a model of graft surgery.