Factor XI and XII inhibitors–Dawn of a new era

Abstract

The history of coagulation cascade dates back to 17th century. The extrinsic and intrinsic pathways were proposed in 1998. Extrinsic pathway includes the tissue factor and stable factor which activates factor X and with help of factor V, this converts prothrombin to thrombin which is stabilised by factor XIII. This helps to seal the bleeding vessel and is a physiological process as there is only “limited” production of thrombin which doe not expand beyond the damaged site due to absence of tissue factor. On the other hand intrinsic pathway is activated by polyanions, neutrophilic extracellular traps which are present during infection and inflammation. These activate factor XI which activates factor X with the help of factor IX and VIII and then the common pathway ensues. But newer discoveries have shown that this is a very simplified way of explaining the coagulation system. The researches propose that haemostasis is divided into initiation, amplification and propagation phase. Also, the factor VII-tissue factor complex formed activates factor IX and leads to sustained thrombin production as the amount of thrombin produced by extrinsic pathway alone is not sufficient to form a haemostatic plug. Thrombin also activates factor XI and lead to self perpetuation of intrinsic pathway.

All the anticoagulants have an inherent property of bleeding. So the newer factor XI and XII inhibitors focus to inhibit the excessive thrombin production without hampering the physiological haemostasis process. This is supported by the fact that congenital factor XI and XII deficiency does not cause excessive bleeding but increased levels did make patients more vulnerable to thromboembolism.

This review shall focus on the various factor XI and XII inhibitors which are in the pipeline.