Factors IX, XI, and XII: potential therapeutic targets for anticoagulant therapy in atherothrombosis

Abstract

Atherosclerosis is a leading cause of cardiovascular and neurological ischemic events. Plaque rupture leads to the exposure of highly thrombogenic material with blood and results in the activation of the coagulation cascade, thrombus formation, and embolic events. Although antiplatelets and anticoagulants are used to prevent thromboembolic episodes, bleeding episodes remain the major adverse effect. Decreased ischemic events have been reported while comparing oral rivaroxaban and apixaban with aspirin to improve the therapeutic outcome in several clinical trials, including Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome-Thrombolysis in Myocardial Infarction 51, Apixaban for Prevention of Acute Ischemic and Safety Events, and GEMINI-ACS-1 phase II clinical trials. However, there were bleeding episodes. Thus, there is an unmet need for better therapeutic strategies. Therefore, the current focus is to target Factors IX, XI, and XII to develop safer and efficient strategies. In this article, we critically reviewed and discussed the limitations of current therapies and the potential of targeting Factors IX, XI, and XII for anticoagulant therapy in atherothrombosis.

Smart thrombosis inhibitors without bleeding side effects via charge tunable ligand design

“…Indeed, to date, there is no effective antithrombotic drug available that is not complicated by a bleeding risk. Recent investigations on FXIa inhibition and FXIIa inhibitors are promising but not yet approved for clinical use 9 , 53 . Research over the last decade revealed that procoagulant polyanions including polyP are valid targets toward the development of safer antithrombotics 5 , 6 , 54 – 56 .…”

Thromboembolism in the Complications of Long COVID-19

“…The molecular mechanisms of the link between aPL and thromboembolism in patients with COVID-19 have yet to be elucidated. However, vascular endothelial damage inducing thrombin generation and excessive proinflammatory cytokines such as interleukins IL-1β and IL-6, TNFα, complement proteins, and coagulation factors among other immunologic mechanisms may produce activation of coagulopathies [ 16 , 21 , 35 ]. Further studies are needed to determine the extent of the link between aPLs and thromboembolism post-COVID-19 and the mechanisms by which thromboembolism is induced.…”

“…With COVID-19 constantly evolving, it has been difficult to extrapolate the relationship between COVID-19 and thrombotic events, specifically Arterial Thromboembolism (ATE) and Venous Thromboembolism (VTE) in patients who have acute- and long-term COVID-19. It is very likely that COVID-19 infection affects coagulation factors IX, XI, and XII and several immune cell functions resulting in atherothrombosis [ 16 – 18 ]. Thrombotic events for ATE could also be due to destabilization of atherosclerotic plaque resulting in limb arterial thrombosis, transient ischemic attack and stroke, cerebral infarction, and myocardial infarction [ 5 , 19 , 20 ].…”

Pulmonary embolism: update on management and controversies

“…Anticoagulant therapies targeting coagulation factors IX, XI, and XII are under research and development 166167. Of these, factor XIa inhibition is most developed and includes targeted strategies such as antisense oligonucleotide agents to reduce hepatic biosynthesis, aptamers to target DNA or RNA expression, and monoclonal antibodies and small molecules that block activity of factor XIa 168169.…”