Factor XI inhibition fulfilling the optimal expectations for ideal anticoagulation

Abstract

Introduction: Thromboembolic diseases are leading cause of mortality accounting for an estimated 1 in 4 deaths all over the world. Anticoagulation remains the mainstay of prevention and treatment of venous thromboembolic disorders. Conventional anticoagulants have been efficiently used over the last decades, but their clinical use encounters safety and convenience issues. To overcome these limitations, research have focused on development of new targets for anticoagulation leading to a relatively new class of drugs, non-vitamin K antagonist oral anticoagulants, specifically targeting activated factor X and thrombin.However, the search for more potent anticoagulant agents with reduced bleeding risk is still continuing. Areas covered:In this review, we provide an overview on emerging investigational anticoagulant drugs targeting factor XI in the coagulation cascade. We review data about the role of intrinsic pathway in thrombosis and haemostasis and the rationale of different pharmacodynamic approaches targeting factor XI.Expert opinion: Recent evidence suggests that the contact pathway plays a significant role in thrombosis by thrombus stabilization and growth without perturbing haemostasis. Factor XI might be a promising drug target to develop highly effective antithrombotic therapy with safety bleeding profile. Most of these investigational agents are in early development phases, only few have reached early phase clinical trials.

Activated Factor XI is Increased in Plasma in Response to Surgical Trauma but not to Recombinant Activated FVII-Induced Thrombin Formation

“…This indicates ongoing FXIa formation even after the formation of a woundsealing clot. Moreover, it may indicate that FXIa contributes to the postoperative procoagulant state and supports an anticoagulant approach that targets FXIa 20,42) .…”

“…Recent evidence that suggests that the contact pathway may play a significant role in the development of thrombosis via thrombus stabilization and growth promotion has led to the investigation of FXI and FXIa as potential new drug targets to achieve safer anticoagulation 20,21) . Novel pharmacologic strategies that target FXI and FXIa include antisense oligonucleotides and monoclonal antibodies, which act by blocking the activation or activity of the coagulation factor, and aptamers and small molecules that block the active site or induce allosteric modulation of the protein 22,23) .…”

Factor XIa Inhibition: Is It a Novel Alternative Antithrombotic Strategy for High-Risk ACS Patients?

“…9 Other FXIa inhibitors such as IONIS-416858 and AB023 are in development, or tested in various clinical settings. 10 In this issue of Circulation, the investigators of the PACIFIC-AMI (Proper Dosing and Safety of the Oral FXIa Inhibitor BAY 2433334 in Patients Following an Acute Heart Attack) trial report on the pharmacodynamics, safety, and efficacy of adding asundexian to DAPT in patients with recent myocardial infarction. 11 In this phase 2, randomized double-blind trial, patients with ACS considered to be at high ischemic risk (defined as meeting at least 1 of the following criteria: ≥65 years of age; previous myocardial infarction, peripheral arterial disease, or coronary artery bypass grafting; diabetes) but without increased risk of bleeding, were randomized within 5 days of the index ACS event to asundexian 10, 20, or 50 mg, or a placebo once daily for up to 12 months.…”

“…9 Other FXIa inhibitors such as IONIS-416858 and AB023 are in development, or tested in various clinical settings. 10…”

Impaired Spontaneous/Endogenous Fibrinolytic Status as New Cardiovascular Risk Factor?

“…There is abundant data that PCSK 9 plasma levels relate to enhanced platelet reactivity, (97) and also regulate coagulation as shown by a correlation with plasma TF levels,(( 98 A number of novel antithrombotic drugs are in development, (103) some with effects on the fibrinolytic system.…”