TARGETING ACTIVATED FACTOR XII (FXIIa)
Inhibition of FXIIa will:
Shut down the intrinsic pathway of coagulation
Prevent activation of the positive feedback loop, through which Factor XIIa can activate kallikrein that in turn generates more Factor XIIa
Prevent the bypass of Factor XI created by direct activation of Factor IX by kallikrein
(Arterioscler Thromb Vasc Biol. 2020 Jan;40(1):103-111 & Blood. 2020 Jan 22. pii: blood.2019001643. doi: 10.1182/blood.2019001643)
The pleiotropic effects of Factor XIIa inhibition are illustrated below
There are two distinct pathways for initiating blood coagulation, known as the ‘extrinsic’ and ‘intrinsic’ pathways, that converge on a common pathway leading to thrombin generation and fibrin formation. The intrinsic pathway is initiated when Factor XII comes into contact with negatively charged surfaces resulting in ‘contact activation’, which also involves the plasma proteins (Pre)kallikrein and high-molecular-weight kininogen. Contact activation initiates a cascade of proteolytic events, ultimately resulting in thrombin generation and fibrin clot formation.
Inhibition of activated Factor XII (FXIIa) in the intrinsic pathway of blood coagulation provides the opportunity to generate antithrombotic agents with enhanced potency and an unprecedented therapeutic index for the incidence of uncontrolled bleeding events.
LUNAC has demonstrated that FXIIa exerts a range of pleiotropic events both within the intrinsic pathway, and in clot propagation, leaving the extrinsic pathway unopposed in its ability to reinforce haemostasis.