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 circulating blood, providing a limited amount of thrombin molecules that activate a number of coagulation proteins as well as the platelets. As a result of activation with thrombin the platelet surface exposes negatively charged phospholipids to which activated coagulation proteins bind tightly, and full thrombin generation occurs, resulting in the conversion of fibrinogen into fibrin. After the first FXa is formed, the tissue factor pathway inhibitor (TFPI) forms a complex with FXa. In the next step a quaternary complex is being formed, TF/FVIIa/FXa/TFPI, which inhibits the first step of the haemostatic pathway. Recombinant FVIIa (rFVIIa) has been developed for use as a haemostatic 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 models 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 thickening. Also, topical application of rFVIIai was found to block the formation of a thrombus. rFVIIai was shown to have an anti-inflammatory effect in lipopolysaccharide (LPS)-induced sepsis, and postischaemic reperfusion injury was found to be reduced by the administration of rFVIIai. In a limited number of patients undergoing percutaneous transluminal coronary angioplasty (PTCA), rFVIIai was observed to allow PTCA to be performed at lower doses of heparin than what has been reported previously. Recombinant TFPI has been shown to attenuate the lethal inflammatory and coagulopathic response. Furthermore, topical application of rFVIIai has been found to increase the patency rate in a model of graft surgery.