Blocking the initiation of coagulation by RNA aptamers to factor VIIa

The tissue factor/factor VIIa complex is thought to be the primary initiato r of most physiologic blood coagulation events. Because of its proximal rol e in this process, we sought to generate new inhibitors of tissue factor/fa ctor VIIa activity by targeting factor VIIa. We employed a combinatorial RN A library and in vitro selection methods to isolate a high affinity, nuclea se-resistant RNA ligand that binds specifically to coagulation factor VII/V IIa. This RNA inhibits the tissue factor-dependent activation of factor X b y factor VIIa. Kinetic analyses of the mechanism of action of this RNA sugg est that it antagonizes factor VIIa activity by preventing formation of a f unctional factor VII/tissue factor complex. Furthermore, this RNA significa ntly prolongs the prothrombin time of human plasma in a dose dependent mann er, and has an ill vitro half-life of similar to 15 h in human plasma. Thus , this RNA ligand represents a novel class of anticoagulant agents directed against factor VIIa.