Factor Xa Is a Superior Target to Factor IIa for Antithrombotic Therapies

At least five arguments can be put forward to support the concept that selective inhibitors of factor Xa might be superior to selective inhibitors of thrombin. It should be noted, however, that most of these arguments are theoretical and that the issue can only be resolved by head-to-head comparisons. Another word of caution is warranted about whether these new compounds should be considered as a class of drugs or as individual agents. Although direct inhibitors may differ from indirect inhibitors in terms of their clinical efficacy and safety, it is not possible to distinguish this at present. Hence, in this short article, factor Xa inhibitors are considered as a class rather than as individual compounds.

The first argument is practical. The coagulation cascade can be likened to a river. The easiest place to dam a river is upstream, close to the source. When the coagulation cascade is activated, the amount of product formed in the individual reactions increases logarithmically at each step of the cascade. Conceptually, it is thus more attractive to inhibit the process upstream, that is, at the level of the tissue factor/factor VIIa complex or at factor Xa itself.

The second argument relates to differences in opinion regarding the importance of thrombin in the coagulation cascade. The “thrombin dogma” considers thrombin to be at the heart of the coagulation cascade, the final common pathway. This assumption is based predominantly on outdated interpretations of the intrinsic and extrinsic pathways of coagulation activation. The current view is that the tissue factor/factor VIIa complex and factor Xa play a more prominent role. This view is encapsulated in a quotation from a review by Mann and associates in 1998: “Under normal circumstances, the rate limiting component of most prothrombinase formation and the generation of thrombin activity is the concentration of factor Xa.”[1] Thus, control of factor Xa appears to be the ideal target for limiting the subsequent generation of thrombin, rather than inhibition of thrombin itself.

The third argument supporting the importance of factor Xa inhibition concerns the dual role of thrombin. At low concentrations, thrombin exhibits antithrombotic properties through binding to thrombomodulin and formation of activated protein C (APC). Hence, generation of small amounts of thrombin despite maximum inhibition of factor Xa is not a drawback. At higher thrombin concentrations, the balance becomes more prothrombotic and antifibrinolytic.

The fourth argument concerns enzyme-kinetic considerations. In humans, the ratio of the concentrations of the zymogens prothrombin and factor X is ~10:1. Furthermore, one molecule of factor Xa generates ~100 molecules of thrombin in 1 second. It is probably for this reason that the APC system evolved. It is interesting to note that, to control factor Xa via the APC pathway, factor VIII is inhibited with consequent down-regulation of factor Xa formation, while the APC-mediated inhibition of factor Va decreases the efficacy of factor Xa. If nature made control of factor Xa so important, why would pharmacologic inhibition not be ideal?

The final argument comes from clinical observations. Although thus far no studies compared pure factor Xa inhibition with selective thrombin inhibition, the prophylaxis studies with the synthetic pentasaccharide fondaparinux (an indirect factor Xa inhibitor) versus low-molecular-weight heparin confirmed the hypothesis that selective inhibition of factor Xa is very effective. Indeed, these studies showed a more than 50% reduction in rates of venographic deep vein thrombosis relative to the mixed factor Xa and thrombin inhibition of low-molecular-weight heparin. The outstanding efficacy of factor Xa inhibition is further supported by Phase II data, mostly unpublished to date, of selective and direct factor Xa inhibitors.

These new compounds will allow more sophisticated control of unwanted thrombosis. We remain indebted to the efforts of numerous scientists who have helped increase our understanding of the coagulation system.

REFERENCE

• 1 Jenny N S, Mann K G. Coagulation cascade; an overview. In: Loscalzo J, Schafer AI, eds. Thrombosis and Hemorrhage Baltimore, MD: Williams & Wilkins 1998: 3-27