The Role of the Contact Pathway in Thrombus Propagation

Abstract

The continued search for the ideal antithrombotic agent that would prevent or reduce thrombus growth inside blood vessels without an effect on the essential hemostatic functions of blood, including extraluminal thrombin generation and platelet activation, has been going in new directions in the past decade. These directions include studies suggesting that activation of the intrinsic coagulation cascade through contact activation of factor XII, and the resultant thrombin generation is a pathologic event that leads to undesirable consequences. Recent animal studies of contact pathway inhibitors in experimental thrombogenesis suggest that the contact activation pathway of blood coagulation may play a pathogenic role in thrombosis, and pharmacologic inhibition of contact activation may have antithrombotic effects. Development of reasonably potent selective inhibitors of contact activation pathway components or activities now allow for the conduct of studies in various animal species, including primates. These studies have generated interesting data that now support the hypothesis that thrombogenesis in humans may also involve the pathological activation of the intrinsic coagulation cascade. Moreover, baboons, mice, and rabbits, pretreated with antibodies that selectively inhibit factor XII activation, procoagulant factor XIIa activity, or all enzymatic activities of factor XIIa show significantly reduced propensity for occlusive thrombus propagation in various models of acute thrombogenesis on vascular grafts, membrane oxygenators, and even on injured arteries. Since contact activation of blood does not play a demonstrable role in normal hemostasis, and there has been no evidence generated to date suggesting that activation of factor XII has a physiologic function, current research now supports the original concept, developed over 2 decades ago, that temporal pharmacologic inhibition of thrombin generation through the contact pathway may have therapeutic potential and could produce beneficial antithrombotic activities without hemostasis impairment.