Science
FACTOR IX AS AN INNOVATIVE AND ADVANTAGEOUS TARGETBlood coagulation (clotting) is initiated and maintained by a set of proteins in the blood, called coagulation factors, and platelets. Coagulation Factor IX is unique in this process, as it is involved in both the initiation of coagulation and the propagation phase when the clot is formed.Blood coagulation is a complex process, involving different subsets of coagulation factors during each of three phases: initiation, amplification and propagation. 1. InitiationTissue Factor (TF) within the blood vessel lining is exposed following damage to the vessel wall, allowing it to form a complex with Factor VIIa. The TF:Factor VIIa complex then activates Factors IX and X, which in turn generate a small amount of thrombin, another coagulation factor.
2. AmplificationThrombin activates coagulation Factors V, VIII and XI, as well as platelets, setting the stage for the propagation phase of coagulation.
3. PropagationThe propagation phase of clot formation takes place on the surface of these activated platelets, and is the phase in which explosive thrombin generation occurs and the stable blood clot is formed. On the surface of the activated platelet, Factor IXa, together with its cofactor Factor VIIIa, activates Factor X to FXa. Subsequently, Factor Xa forms a complex with Factor Va to cleave prothrombin into thrombin, which in turn generates fibrin, the protein that creates the mesh essential to clot formation.
FIXa is the rate limiting factor in thrombin generation, and in complex with its cofactor VIIIa, is the sole catalyst for generation of FXa on the activated platelet surface, making it an attractive target for development of an anticoagulant agent. FIXa is approximately 7-fold more thrombogenic than FXa and 60-fold more thrombogenic than thrombin, and the critical role of FIXa in arterial and venous thrombus generation has been demonstrated in knock-out mice, and in multiple therapeutic and prophylactic thrombosis models employing anti-FIX monoclonal antibodies or inactivated forms of FIXa as therapeutic agents. Epidemiologic studies have demonstrated that increased FIX levels are a risk factor for ACS and venous thromboembolic disease, and that elevated levels of FIXa are predictive of incident myocardial infarctions, further validating FIXa as a target for the treatment of both arterial and venous thrombotic disease. In addition, given its relatively low abundance compared to FXa or thrombin, complete inhibition of plasma FIXa activity is possible with pharmacologic intervention. Despite the attractiveness of FIXa as a target for development of novel anticoagulants, it has been a challenging target for the development of small molecule inhibitors due to conformational heterogeneity of its active site in the absence of association with FVIIIa. Regado’s use of the aptamer technology to generate inhibitors of FIXa that directly block its interaction with its protein pairing partners has unlocked FIXa as an anticoagulant target. |
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