Inhibition of Factor VIta / Tissue Factor - Induced Blood Coagulation : With Particular Emphasis Upon a Factor Xa - Dependent Inhibitory Mechanism

T HREE ENZYME/COFACTOR complexes form on cell surfaces in tightly regulated reactions during normal blood coagulation in vivo. The enzymes of these complexes, factor VIla, factor IXa, and factor Xa, are ancestrally related serine proteases that are members of the vitamin K-dependent group of clotting factors. Each is generated during blood coagulation by limited proteolysis of a zymogen precursor. Highly efficient when associated with its cofactor, each enzyme is physiologically inert in the absence of its cofactor. The cofactor for factor Vila is tissue factor, a protein present constitutively in the surface membrane of certain tissue cells, including pericytes and fibroblasts in the adventitia of blood vessels, and appearing transiently, after their activation, in the plasma membrane of two cells to which circulating blood is exposed, vascular endothelium and monocytes. The properties of tissue factor that require association with phospholipid provided in vivo by the lipid bilayer of the surface membrane for its activity, have been summarized in a recent review.’ A factor VII(a)/tissue factor (TF) complex, which is thought to be the first enzyme/cofactor complex that is formed on cell surfaces during normal blood coagulation in vivo, initiates coagulation through activation of factors IX and X.”2 The cofactor for factor IXa, which is factor Villa, and the cofactor for factor Xa, which is factor Va, have many structural and functional similarities, These have also been recently summarized.3 A factor IXa/factor VIlla/phospholipid vesicle (in soluble systems) or membrane equivalent (on cell surfaces) complex serves as a second activator of factor x, The bleeding of patients with severe hemophilia, who cannot form this second activator, attests to its importance for normal blood coagulation during hemostasis, The third enzyme/cofactor complex, an analagous factor Xa/factor Va/phospholipid vesicle or membrane equivalent complex, is the only known physiologic activator of prothrombin. Much has been learned about the regulatory mechanisms modulating formation of the second and third complexes.4’5 The proteinase inhibitor, antithrombin III, in the presence of negatively charged, sulfated glycosaminoglycans such as heparin or heparan sulfate, can efficiently neutralize both factor IXa and factor Xa. Activated protein C, with the help of protein S. inactivates both factor Villa and factor Va. Clinical experience, the failure ever to identify a live infant with homozygous antithrombin III deficiency and the fulminant thrombotic disease of the rare infant born totally deficient in protein C,6’7 teaches us that major break downs of their function are incompatible with life. Within the last 5 years interest in a mechanism regulating the activity of the factor VIIa/TF complex has reawakened. The mechanism differs basically from the reactions regulating the activity of the other enzyme/cofactor complexes. Antithrombin III inhibits factors IXa and Xa, and activated protein C inhibits factors Villa and Va more effectively before, rather than after, they form enzyme/cofactor complexes.8’9 In contrast, a factor VII(a)/TF complex must form and catalyze beginning activation of factor X before the reactions inhibiting further factor VIIa/TF catalytic activity are triggered. These involve the participation of a plasma inhibitor that was given the provisional name extrinsic pathway inhibitor (EPI) by one group’#{176}and the name lipoprotein-associated coagulation inhibitor (LACI) by another.” Recently, the inhibitor has been identified as a proteinase inhibitor belonging to the basic protease inhibitor gene superfamily.’2 The term EPI will be used in this review, which should be looked upon as an “interim summary” at an early stage of our understanding of the properties of EPI, of its mechanism of action in inhibiting factor VIIa/TF catalytic activity, and of the potential physiologic significance of EPI-induced inhibition for the regulation of blood coagulation. Other biologic materials reported to be capable of inhibiting factor VIIa/TF catalytic activity’3”5 will be discussed briefly.