The foundation for investigating factor XI as a target for inhibition in human cardiovascular disease

Abstract

Anticoagulant therapy is a mainstay in the management of patients with cardiovascular disease and related conditions characterized by a heightened risk for thrombosis. Acute coronary syndrome, chronic coronary syndrome, ischemic stroke, and atrial fibrillation are the most common. In addition to their proclivity for thrombosis, each of these four conditions is also characterized by local and systemic inflammation, endothelial/endocardial injury and dysfunction, oxidative stress, impaired tissue-level reparative capabilities, and immune dysregulation that plays a critical role in linking molecular events, environmental triggers, and phenotypic expressions. Knowing that cardiovascular disease and thrombosis are complex and dynamic, can the scientific community identify a common pathway or specific point of interface susceptible to pharmacological inhibition or alteration that is likely to be safe and effective? The contact factors of coagulation may represent the proverbial "sweet spot" and are worthy of investigation. The following review provides a summary of the fundamental biochemistry of factor XI, its biological activity in thrombosis, inflammation, and angiogenesis, new targeting drugs, and a pragmatic approach to managing hemostatic requirements in clinical trials and possibly day-to-day patient care in the future.

Keywords: Factor XI; Hemostasis; Monoclonal antibodies; Small molecule inhibitors.

Fig. 1

The intrinsic pathway of coagulation also referred to as the contact pathway is initiated following exposure of blood to negatively charged surfaces. The are a series of biochemical/enzymatic steps that follow, including activation of factors XII, XI, IX, and VIII that in complex with factor X (prothrombinase complex), and phospholipid convert prothrombin to thrombin (factor IIa). Thrombin then catalytically converts fibrinogen to fibrin- the predominant structural protein in a thrombus

Fig. 2

Role of factor XI in thrombosis. Factor XI is particularly important for thrombin generation following activation of the intrinsic pathway of coagulation (see text). “Created with BioRender.com”

Fig. 3

Role of factor XI in hemostasis (see text). Factor XI plays an important role in thrombus consolidation and feedback activation following thrombin activation through the extrinsic or tissue factor pathway of coagulation. “Created with BioRender.com”